22-37226735-T-G

Position:

• chr22-37226735-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002872.5(RAC2):​c.517A>C​(p.Ile173Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAC2 NM_002872.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAC2	NM_002872.5	c.517A>C	p.Ile173Leu	missense_variant	6/7	ENST00000249071.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAC2	ENST00000249071.11	c.517A>C	p.Ile173Leu	missense_variant	6/7	1	NM_002872.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neutrophil immunodeficiency syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1375066). This variant has not been reported in the literature in individuals affected with RAC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 173 of the RAC2 protein (p.Ile173Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Uncertain	-0.061	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.015	D;D;D
Polyphen		0.41	B;.;.
Vest4		0.66
MutPred		0.67		Gain of catalytic residue at I173 (P = 0.0447);.;.;
MVP		0.61
MPC		0.082
ClinPred		0.92	D
GERP RS		4.9
Varity_R		0.84
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-37622775;