rs1064498

Positions:

• chr22-37226775-A-G
• chr22-37226775-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002872.5(RAC2):​c.477T>C​(p.Ala159=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,612,120 control chromosomes in the GnomAD database, including 22,937 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4567 hom., cov: 31)
  • Exomes 𝑓: 0.15 (18370 hom.)
• Consequence: RAC2 NM_002872.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.935

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 22-37226775-A-G is Benign according to our data. Variant chr22-37226775-A-G is described in ClinVar as [Benign]. Clinvar id is 138864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37226775-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.935 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAC2	NM_002872.5	c.477T>C	p.Ala159=	synonymous_variant	6/7	ENST00000249071.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAC2	ENST00000249071.11	c.477T>C	p.Ala159=	synonymous_variant	6/7	1	NM_002872.5	P1

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33043 AN: 151414 Hom.: 4554 Cov.: 31

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.293

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.212

GnomAD3 exomes AF: 0.164 AC: 41061 AN: 250422 Hom.: 4256 AF XY: 0.159 AC XY: 21614 AN XY: 135562

Gnomad AFR exome AF: 0.403

Gnomad AMR exome AF: 0.0912

Gnomad ASJ exome AF: 0.201

Gnomad EAS exome AF: 0.298

Gnomad SAS exome AF: 0.101

Gnomad FIN exome AF: 0.148

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.150 AC: 219192 AN: 1460588 Hom.: 18370 Cov.: 33 AF XY: 0.148 AC XY: 107765 AN XY: 726634

Gnomad4 AFR exome AF: 0.397

Gnomad4 AMR exome AF: 0.0992

Gnomad4 ASJ exome AF: 0.199

Gnomad4 EAS exome AF: 0.285

Gnomad4 SAS exome AF: 0.105

Gnomad4 FIN exome AF: 0.148

Gnomad4 NFE exome AF: 0.141

Gnomad4 OTH exome AF: 0.179

GnomAD4 genome AF: 0.218 AC: 33092 AN: 151532 Hom.: 4567 Cov.: 31 AF XY: 0.216 AC XY: 16007 AN XY: 74048

Gnomad4 AFR AF: 0.394

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.202

Gnomad4 EAS AF: 0.292

Gnomad4 SAS AF: 0.122

Gnomad4 FIN AF: 0.150

Gnomad4 NFE AF: 0.144

Gnomad4 OTH AF: 0.213

Alfa AF: 0.153 Hom.: 1194

Bravo AF: 0.227

Asia WGS AF: 0.219 AC: 760 AN: 3478

EpiCase AF: 0.150

EpiControl AF: 0.153

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 21% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -

Neutrophil immunodeficiency syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.7
DANN	Benign	0.65

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: rs1064498; hg19: chr22-37622815; COSMIC: COSV50773917;