1. Panels
  2. Intellectual disability
  3. PRKACB
Genes in panel
Prev Next
Regions in panel
Prev Next

Intellectual disability

Gene: PRKACB

Amber List (moderate evidence)
PRKACB (protein kinase cAMP-activated catalytic subunit beta)
EnsemblGeneIds (GRCh38): ENSG00000142875
EnsemblGeneIds (GRCh37): ENSG00000142875
OMIM: 176892, Gene2Phenotype
PRKACB is in 5 panels

3 reviews

Achchuthan Shanmugasundram (Genomics England Curator)

I don't know

Comment on list classification: In total, three of five unrelated cases reported with PRKACB variants had intellectual disability, of which one had mild ID. Hence, it should still be rated amber. The 'watchlist' tag has been added to look out for new evidence in the future.
Created: 19 Sep 2024, 1:54 p.m. | Last Modified: 19 Sep 2024, 2:57 p.m.
Panel Version: 7.35
PMID:39095811 paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.

This paper reported the identification of a de novo missense variant in PRKACB on ES re-analysis in an individual with intellectual disability, refractory focal epilepsy, spasticity, periventricular nodular heterotopia, a common atrium / AVSD, polydactyly and several tumours.
Created: 19 Sep 2024, 1:49 p.m. | Last Modified: 23 Sep 2024, 9:45 a.m.
Panel Version: 7.39

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

Created: 19 Sep 2024, 1:49 p.m.
Last Modified: 23 Sep 2024, 9:45 a.m.
Panel version: 7.35

Arina Puzriakova (Genomics England Curator)

Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber based on the evidence provided in one publication (PMID:33058759) reporting 2/4 unrelated individuals with ID among other features, although this presentation was mild in one of these cases.
Created: 19 Nov 2020, 1:47 p.m. | Last Modified: 19 Nov 2020, 1:47 p.m.
Panel Version: 3.551
Created: 19 Nov 2020, 1:47 p.m.
Last Modified: 19 Nov 2020, 1:47 p.m.
Panel version: 3.551

Konstantinos Varvagiannis (Other)

I don't know

ID was a feature in 2/4 individuals with PRKACB pathogenic variant reported to date.

Please consider inclusion of PRKACB (and PRKACA) in other relevant gene panels e.g. for polydactyly, congenital heart defects. The disorder may be considered in the DD of ciliopathies.

-----


Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 3 individuals heterozygous for PRKACA and 4 individuals heterozygous for PRKACB pathogenic variants.

The most characteristic features in all individuals with PRKACA/PRKACB mutation, included postaxial polydactyly of hands (6/7 bilateral, 1/7 unilateral) and feet (4/7 bilateral, 1/7 unilateral), brachydactyly and congenital heart defects (CHD 5/7) namely a common atrium or AVSD. Two individuals with PRKACA variant who did not have CHD had offspring with the same variant and an AVSD.

Other variably occurring features included short stature, limbs, narrow chest, abnormal teeth, oral frenula, nail dysplasia. One individual with PRKACB variant presented tumors.

Intellectual disability was reported in 2/4 individuals with PRKACB variant (1/4: mild, 1/4: severe). The 3 individuals with PRKACA variant did not present ID.

As the phenotype was overall suggestive of Ellis-van Creveld syndrome (or the allelic Weyers acrofacial dysostosis), although these diagnoses were ruled out following analysis of EVC and EVC2 genes.

WES was carried out in all.

PRKACA : A single heterozygous missense variant was identified in 3 individuals from 3 families (NM_002730.4:c.409G>A / p.Gly137Arg) with 1 of the probands harboring the variant in mosaic state (28% of reads) and having 2 similarly affected offspring. The variant was de novo in one individual and inherited in a third one having a similarly affected fetus (narrow thorax, postaxial polyd, AVSD).

PRKACB : 4 different variants were identified (NM_002731.3: p.His88Arg/Asn, p.Gly235Arg, c.161C>T - p.Ser54Leu). One of the individuals was mosaic for the latter variant, while in all other cases the variant had occurred de novo.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes.

The authors provide evidence that the variants confer increased sensitivity of PKA holoenzymes to activation by cAMP (compared to wt).

By performing ectopic expression of wt or mt PRKACA/B (variants studied : PRKACA p.Gly137Arg / PRKACB p.Gly235Arg) in NIH 3T3 fibroblasts, the authors demonstrate that inhibition of hedgehog signaling likely underlyies the developmental defects observed in affected individuals.

As for PRKACA, the authors cite another study where a 31-month old female with EvC syndrome diagnosis was found to harbor the aforementioned variant (NM_001304349.1:c.637G>A:p.Gly213Arg corresponding to NM_002730.4:c.409G>A / p.Gly137Arg) as a de novo event. Without additional evidence at the time, the variant was considered to be a candidate for this subject's phenotype (Monies et al 2019 – PMID: 31130284).
Sources: Literature
Created: 24 Oct 2020, 11:09 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability

Publications

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Created: 24 Oct 2020, 11:09 p.m.

Panel version: 3.484

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
Phenotypes
  • Cardioacrofacial dysplasia 2, OMIM:619143
Tags
watchlist
OMIM
176892
Clinvar variants
Variants in PRKACB
Penetrance
unknown
Publications
Mode of Pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Panels with this gene

History Filter Activity

19 Sep 2024, Gel status: 2

Set publications

Achchuthan Shanmugasundram (Genomics England Curator)

Publications for gene: PRKACB were set to 33058759

19 Sep 2024, Gel status: 2

Set mode of inheritance

Achchuthan Shanmugasundram (Genomics England Curator)

Mode of inheritance for gene: PRKACB was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

19 Sep 2024, Gel status: 2

Entity classified by Genomics England curator

Achchuthan Shanmugasundram (Genomics England Curator)

Gene: prkacb has been classified as Amber List (Moderate Evidence).

19 Sep 2024, Gel status: 2

Added Tag

Achchuthan Shanmugasundram (Genomics England Curator)

Tag watchlist tag was added to gene: PRKACB.

22 May 2023, Gel status: 2

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: PRKACB were changed from Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability to Cardioacrofacial dysplasia 2, OMIM:619143

19 Nov 2020, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: prkacb has been classified as Amber List (Moderate Evidence).

24 Oct 2020, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance, Set mode of pathogenicity

Konstantinos Varvagiannis (Other)

gene: PRKACB was added gene: PRKACB was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PRKACB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PRKACB were set to 33058759 Phenotypes for gene: PRKACB were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability Penetrance for gene: PRKACB were set to unknown Mode of pathogenicity for gene: PRKACB was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: PRKACB was set to AMBER