rs2230919

Positions:

• chr22-37231968-G-A

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.252C>T​(p.Leu84=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00427 in 1,552,320 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (71 hom., cov: 31)
  • Exomes 𝑓: 0.0027 (52 hom.)
• Consequence: RAC2 NM_002872.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.57

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=-0.57).
• BP6: Variant 22-37231968-G-A is Benign according to our data. Variant chr22-37231968-G-A is described in ClinVar as [Benign]. Clinvar id is 378454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37231968-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAC2	NM_002872.5	c.252C>T	p.Leu84=	synonymous_variant	4/7	ENST00000249071.11
RAC2	XM_006724286.4	c.252C>T	p.Leu84=	synonymous_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAC2	ENST00000249071.11	c.252C>T	p.Leu84=	synonymous_variant	4/7	1	NM_002872.5	P1

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2844 AN: 152024 Hom.: 71 Cov.: 31

Gnomad AFR AF: 0.0617

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00950

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00510 AC: 804 AN: 157696 Hom.: 13 AF XY: 0.00420 AC XY: 349 AN XY: 83102

Gnomad AFR exome AF: 0.0628

Gnomad AMR exome AF: 0.00479

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000438

Gnomad FIN exome AF: 0.000850

Gnomad NFE exome AF: 0.00137

Gnomad OTH exome AF: 0.00495

GnomAD4 exome AF: 0.00269 AC: 3763 AN: 1400178 Hom.: 52 Cov.: 31 AF XY: 0.00248 AC XY: 1710 AN XY: 690708

Gnomad4 AFR exome AF: 0.0608

Gnomad4 AMR exome AF: 0.00514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000559

Gnomad4 SAS exome AF: 0.000378

Gnomad4 FIN exome AF: 0.00122

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.00520

GnomAD4 genome AF: 0.0188 AC: 2861 AN: 152142 Hom.: 71 Cov.: 31 AF XY: 0.0188 AC XY: 1399 AN XY: 74374

Gnomad4 AFR AF: 0.0619

Gnomad4 AMR AF: 0.00948

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000832

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00152

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00755 Hom.: 11

Bravo AF: 0.0210

Asia WGS AF: 0.00404 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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	GeneDx	Jul 24, 2015	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. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Neutrophil immunodeficiency syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	4.8
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2230919; hg19: chr22-37628008;