chr22-37232857-C-T

Position:

• chr22-37232857-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_002872.5(RAC2):​c.169G>A​(p.Asp57Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAC2 NM_002872.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• 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]

RAC2 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 22-37232857-C-T is Pathogenic according to our data. Variant chr22-37232857-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7575.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAC2	NM_002872.5	c.169G>A	p.Asp57Asn	missense_variant	3/7	ENST00000249071.11	NP_002863.1
RAC2	XM_006724286.4	c.169G>A	p.Asp57Asn	missense_variant	3/6		XP_006724349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAC2	ENST00000249071.11	c.169G>A	p.Asp57Asn	missense_variant	3/7	1	NM_002872.5	ENSP00000249071.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Neutrophil immunodeficiency syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 05, 2020	This sequence change replaces aspartic acid with asparagine at codon 57 of the RAC2 protein (p.Asp57Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change disrupts RAC2 protein function in a dominant negative fashion (PMID: 10758162, 10961859, 11278678, 14676277). This variant has been observed to be de novo in an individual affected with neutrophil immunodeficiency syndrome (PMID: 21167572). In addition, it has been reported in other individuals with similar phenotypes (PMID: 10758162, 10961859). ClinVar contains an entry for this variant (Variation ID: 7575). This variant is not present in population databases (ExAC no frequency). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2000	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;D;D;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H;.;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.7	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.016	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;.
Polyphen		0.69	P;.;.;.
Vest4		0.98
MutPred		0.96		Gain of helix (P = 0.132);.;.;Gain of helix (P = 0.132);
MVP		0.83
MPC		3.1
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.99

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: rs74315507; hg19: chr22-37628897;