Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: RAC2

The mode of inheritance of this gene has been approved by the NHS Genomic Medicine Service.

Created: 4 Mar 2022, 10:17 a.m. | Last Modified: 4 Mar 2022, 10:36 a.m.

Panel Version: 2.529

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 4 Mar 2022, 10:17 a.m. | Last Modified: 4 Mar 2022, 10:17 a.m.

Panel Version: 2.529

Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).

Created: 20 Oct 2020, 3:38 p.m. | Last Modified: 20 Oct 2020, 3:38 p.m.

Panel Version: 2.355

Comment on list classification: Promoted from Amber to Green based on expert review (Zornitza Stark) and evidence.

Created: 21 Apr 2020, 8:19 a.m. | Last Modified: 21 Apr 2020, 8:19 a.m.

Panel Version: 2.106

Green List (high evidence)

Mono-allelic variants: GoF variants reported in at least 5 unrelated individuals, functional data including animal model.
Bi-allelic LoF variants associated with Neutrophil immunodeficiency syndrome, MIM# 608203; Common variable immunodeficiency

Created: 11 Apr 2020, 7:42 a.m. | Last Modified: 11 Apr 2020, 7:42 a.m.

Panel Version: 2.51

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
SCID; recurrent bacterial and viral infections; lymphoproliferation; neutropaenia; reticular dysgenesis; deafness; selective IgA deficiency; Reduced Ab responses following vaccination; Neutrophil immunodeficiency syndrome, MIM# 608203; Common variable immunodeficiency

Publications

• 32198141
• 31919089
• 31382036
• 31071452
• 30723080
• 30654050
• 25512081

Variants in this GENE are reported as part of current diagnostic practice

I don't know

Added publication referenced by IUIS december 2019 update

Created: 28 Feb 2020, 8:49 p.m. | Last Modified: 28 Feb 2020, 8:49 p.m.

Panel Version: 2.36

Comment on mode of inheritance: changed MOI due to IUIS December 2019 update

Created: 28 Feb 2020, 4:46 p.m. | Last Modified: 28 Feb 2020, 4:46 p.m.

Panel Version: 2.28

Original Metadata from IUIS classification table (December, 2019). IUIS Genetic defect (original gene symbol in IUIS download): RAC2 .PanelApp HGNC gene symbol check: RAC2 . IUIS Disease: RAC2 deficiency . IUIS Inheritance: AD GOF / AR / AD LOF, T cells: Very low / no data, .B cells: Very low / no data, Immunoglobulin levels: Low / low, Neutrophil count: Low / High.IUIS Other affected cells: N. IUIS Associated features: Reticular dysgenesis / Recurrent sinopulmonary infections, selective IgA defiency; poststreptococcal glomerulonephritis; urticaria Poor wound healing, leukocytosis, IUIS Major category: TImmunodeficiencies affecting cellular and humoral immunity / Predominantly Antibody Deficiencies / Congenital defects of phagocyte number or function. IUIS Subcategory: T-B- SCID / CVID Phenotype/ Defects of Motility

Created: 28 Feb 2020, 4:45 p.m. | Last Modified: 28 Feb 2020, 4:45 p.m.

Panel Version: 2.27

Added watch list tag. Decided to leave the rating for this gene as Amber, this is borderline, as the Invitae reported variant would make a second case, but there is not enough supporting evidence

Created: 4 Oct 2018, 2:57 p.m.

Zornitza Stark (VCGS) , pers. comm. notes 2 families/functional evidence.
There is only a single variant reported and confirmed in the literature NM_002872.4(RAC2):c.169G>A (p.Asp57Asn) that results in Neutrophil immunodeficiency syndrome PMID: 10758162. There is a second variant reported in clinvar by a Invitae NM_002872.4(RAC2):c.184G>A (p.Glu62Lys), the supporting information denotes "This variant is not present in population databases (ExAC no frequency) and has been shown to arise de novo in an individual affected with severe combined immunodeficiency (Invitae)".

Created: 21 Sep 2018, 12:45 p.m.

PMID: 10961859 reported functional studies demonstrating that the D57N mutant behaves in a dominant-negative fashion at the cellular level.

Created: 21 Sep 2018, 12:29 p.m.

Amber rating. Current literature indicates 1 variants in 3 unrelated families. In OMIM of a relevant phenotype (severe bacterial infections in infancy) is reported. Red ratings highly likely to be historical ratings made prior to further evidence

Created: 11 Jul 2018, 4:01 p.m.

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): RAC2 .PanelApp HGNC gene symbol check: RAC2 . IUIS Disease: RAC2 deficiency . IUIS Inheritance: AD .T cells: Decreased, .B cells: N/A, .IUIS Other affected cells: N. IUIS Associated features: Poor wound healing, leukocytosis. IUIS Major category: Congenital defects of phagocyte number or function. IUIS Subcategory: Defects of Motility

Created: 2 Jul 2018, 10:35 a.m.

This gene was present in the original PanelApp PID panel dataset (review in April 2018) rated as Red. The gene is present in the external expert immunodeficiency diagnostic gene list(s) GOSH or GRID. In this combined PID panel, this gene has been rated as AMBER and needs further curational review to assess pertinence prior to v1.

Created: 20 Apr 2018, 12:25 p.m.

Original metadata downloaded from ESID Registry. ESID_Gene_original: RAC2, PanelApp HGNC gene symbol check: RAC2, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Phagocytic disorders / RAC2-GTPase defect / RAS-related C3 Bolutinum toxin substrate 2 deficiency (RAC2)

Created: 17 Apr 2018, 12:29 p.m.

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: RAC2, GRID_Gene_Symbol: RAC2, GRID_Transcript_ENS_Community submitted: ENST00000249071, GRID_Transcript_RefSeq: NM_002872.3, GRID_Transcript_ENS_used_on_Production: ENST00000249071

Created: 17 Apr 2018, 12:12 p.m.

Publications

• 25512081
• 30723080
• 30654050
• 31071452
• 31382036

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)

Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 2 variants identified in 3 unrelated cases.

Created: 9 May 2018, 2:34 p.m.

Comment when marking as ready: Associated with Neutrophil immunodeficiency syndrome, 608203 in OMIM, no disease association in G2P. Expert review red and 1/4 sources

Created: 25 May 2016, 7:44 a.m.