rs1555908409

Variant names:

• chr22-37232842-C-T
• rs1555908409
• NM_002872.5:c.184G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_002872.5(RAC2):​c.184G>A​(p.Glu62Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E62E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RAC2 NM_002872.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.71
• Publications: 5 publications found

Genes affected

RAC2 (HGNC:9802): (Rac family small GTPase 2) This gene encodes a member of the Ras superfamily of small guanosine triphosphate (GTP)-metabolizing proteins. The encoded protein localizes to the plasma membrane, where it regulates diverse processes, such as secretion, phagocytosis, and cell polarization. Activity of this protein is also involved in the generation of reactive oxygen species. Mutations in this gene are associated with neutrophil immunodeficiency syndrome. There is a pseudogene for this gene on chromosome 6. [provided by RefSeq, Jul 2013]

RAC2 Gene-Disease associations (from GenCC):

• immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen
• immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• neutrophil immunodeficiency syndrome

  Inheritance: Unknown, AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_002872.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 5 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.592 (below the threshold of 3.09). Trascript score misZ: 2.9101 (below the threshold of 3.09). GenCC associations: The gene is linked to immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia, immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia, neutrophil immunodeficiency syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 22-37232842-C-T is Pathogenic according to our data. Variant chr22-37232842-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 464885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAC2	NM_002872.5	c.184G>A	p.Glu62Lys	missense_variant	Exon 3 of 7	ENST00000249071.11	NP_002863.1
RAC2	XM_006724286.4	c.184G>A	p.Glu62Lys	missense_variant	Exon 3 of 6		XP_006724349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAC2	ENST00000249071.11	c.184G>A	p.Glu62Lys	missense_variant	Exon 3 of 7	1	NM_002872.5	ENSP00000249071.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461808 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727202

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RAC2: PS2:Very Strong, PM2, PS4:Moderate, PP3, PS3:Supporting -

Nov 19, 2018

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neutrophil immunodeficiency syndrome;C5436549:Immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia;C5436550:Immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia Pathogenic:1

-

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RAC2:NM_002872:exon3, p.Glu62Lys (c.184G>A): This variant has been reported in 1 individual with suspected Combined Immune Deficiency (CID) as de novo (Hsu 2016) and is not present in large control databases. Furthermore, it is a de novo variant in this child, and evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic. -

Immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia Pathogenic:1

Aug 24, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neutrophil immunodeficiency syndrome Pathogenic:1

May 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 62 of the RAC2 protein (p.Glu62Lys). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RAC2 function (PMID: 30723080). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAC2 protein function. ClinVar contains an entry for this variant (Variation ID: 464885). This missense change has been observed in individual(s) with autosomal dominant combined immunodeficiency (PMID: 30723080; Invitae). In at least one individual the variant was observed to be de novo. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;D;D;D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T;D;D;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;.;.;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;.
Polyphen		0.93	P;.;.;.
Vest4		0.92
MutPred		0.89		Gain of ubiquitination at E62 (P = 0.0146);.;.;Gain of ubiquitination at E62 (P = 0.0146);
MVP		0.97
MPC		2.3
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.95
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555908409; hg19: chr22-37628882;