rs1555908409

chr22-37232842-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 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. 12/21 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:6
• Conservation: PhyloP100: 7.71

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 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, 5 uncertain in NM_002872.5
• PM2: Very rare variant in population databases, with high coverage
• 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 [Likely_pathogenic]. Clinvar id is 464885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAC2	NM_002872.5	c.184G>A	p.Glu62Lys	missense_variant	3/7	ENST00000249071.11
RAC2	XM_006724286.4	c.184G>A	p.Glu62Lys	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAC2	ENST00000249071.11	c.184G>A	p.Glu62Lys	missense_variant	3/7	1	NM_002872.5	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 23, 2021

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 24, 2020

- -

Immunodeficiency;C0024312:Lymphopenia;C0085110:Severe combined immunodeficiency disease;C2711630:Combined immunodeficiency;C4023166:Abnormality of T cell physiology;C4023612:Abnormal cellular immune system morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

-

- -

Neutrophil immunodeficiency syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 31, 2022

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. This variant is not present in population databases (gnomAD no frequency). 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). -

See cases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

Dec 21, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2023

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

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;.;.;.
MutationTaster	Benign	1.0	D;D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555908409; hg19: chr22-37628882;