rs3749004

Variant names:

• chr2-167250981-A-G
• rs3749004
• NM_152381.6:c.9589A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-167250981-A-G
• chr2-167250981-A-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_152381.6(XIRP2):​c.9589A>G​(p.Ile3197Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,613,492 control chromosomes in the GnomAD database, including 15,391 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.17 (2754 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12637 hom.)
• Consequence: XIRP2 NM_152381.6 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.272
• Publications: 20 publications found

Genes affected

XIRP2 (HGNC:14303): (xin actin binding repeat containing 2) Enables actin filament binding activity. Predicted to be involved in actin cytoskeleton organization and heart development. Predicted to act upstream of or within cardiac muscle tissue morphogenesis; cell-cell junction organization; and ventricular septum development. Colocalizes with focal adhesion and stress fiber. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042324364).
• BP6: Variant 2-167250981-A-G is Benign according to our data. Variant chr2-167250981-A-G is described in ClinVar as Benign. ClinVar VariationId is 3055980.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIRP2	NM_152381.6	c.9589A>G	p.Ile3197Val	missense_variant	Exon 9 of 11	ENST00000409195.6	NP_689594.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XIRP2	ENST00000409195.6	c.9589A>G	p.Ile3197Val	missense_variant	Exon 9 of 11	5	NM_152381.6	ENSP00000386840.2

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26182 AN: 151812 Hom.: 2743 Cov.: 32

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.138

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.170

GnomAD2 exomes AF: 0.144 AC: 35799 AN: 248954 AF XY: 0.145

Gnomad AFR exome AF: 0.308

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.140

Gnomad EAS exome AF: 0.121

Gnomad FIN exome AF: 0.143

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.124 AC: 181244 AN: 1461562 Hom.: 12637 Cov.: 36 AF XY: 0.126 AC XY: 91258 AN XY: 727094

African (AFR) AF: 0.308 AC: 10290 AN: 33446

American (AMR) AF: 0.131 AC: 5857 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 3671 AN: 26116

East Asian (EAS) AF: 0.124 AC: 4930 AN: 39696

South Asian (SAS) AF: 0.211 AC: 18189 AN: 86254

European-Finnish (FIN) AF: 0.141 AC: 7555 AN: 53412

Middle Eastern (MID) AF: 0.170 AC: 978 AN: 5762

European-Non Finnish (NFE) AF: 0.109 AC: 121541 AN: 1111798

Other (OTH) AF: 0.136 AC: 8233 AN: 60382

GnomAD4 genome AF: 0.173 AC: 26231 AN: 151930 Hom.: 2754 Cov.: 32 AF XY: 0.173 AC XY: 12815 AN XY: 74256

African (AFR) AF: 0.298 AC: 12329 AN: 41434

American (AMR) AF: 0.144 AC: 2204 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 479 AN: 3470

East Asian (EAS) AF: 0.112 AC: 574 AN: 5130

South Asian (SAS) AF: 0.210 AC: 1014 AN: 4822

European-Finnish (FIN) AF: 0.138 AC: 1463 AN: 10594

Middle Eastern (MID) AF: 0.140 AC: 41 AN: 292

European-Non Finnish (NFE) AF: 0.113 AC: 7656 AN: 67904

Other (OTH) AF: 0.169 AC: 356 AN: 2104

Alfa AF: 0.129 Hom.: 4841

Bravo AF: 0.176

TwinsUK AF: 0.105 AC: 391

ALSPAC AF: 0.118 AC: 454

ESP6500AA AF: 0.278 AC: 1086

ESP6500EA AF: 0.111 AC: 924

ExAC AF: 0.148 AC: 17889

Asia WGS AF: 0.173 AC: 603 AN: 3478

EpiCase AF: 0.114

EpiControl AF: 0.110

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

XIRP2-related disorder Benign:1

Nov 06, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.16
DANN	Benign	0.23
DEOGEN2	Benign	0.012	.;T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.53	T;T;T;T
MetaRNN	Benign	0.0042	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.97	.;L;.;.
PhyloP100		0.27
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.040	N;.;N;.
REVEL	Benign	0.011
Sift	Benign	0.26	T;.;T;.
Sift4G	Benign	0.89	.;.;.;T
Polyphen		0.0010	.;B;B;.
Vest4		0.048
MPC		0.019
ClinPred		0.0075	T
GERP RS		-4.1
Varity_R		0.018
gMVP		0.15
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3749004; hg19: chr2-168107491; COSMIC: COSV54700911;