2-167135972-G-A

Position:

• chr2-167135972-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152381.6(XIRP2):​c.472G>A​(p.Glu158Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 1,611,940 control chromosomes in the GnomAD database, including 471 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (34 hom., cov: 32)
  • Exomes 𝑓: 0.020 (437 hom.)
• Consequence: XIRP2 NM_152381.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.164

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]

XIRP2-AS1 (HGNC:40679): (XIRP2 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001642108).
• BP6: Variant 2-167135972-G-A is Benign according to our data. Variant chr2-167135972-G-A is described in ClinVar as [Benign]. Clinvar id is 403612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-167135972-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0154 (2344/152206) while in subpopulation SAS AF= 0.0491 (237/4826). AF 95% confidence interval is 0.044. There are 34 homozygotes in gnomad4. There are 1109 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XIRP2	NM_152381.6	c.472G>A	p.Glu158Lys	missense_variant	3/11	ENST00000409195.6
XIRP2-AS1	NR_046665.1	n.154+4830C>T		intron_variant, non_coding_transcript_variant
XIRP2	NM_001199143.2	c.472G>A	p.Glu158Lys	missense_variant	3/11
XIRP2	NM_001079810.4	c.472G>A	p.Glu158Lys	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XIRP2	ENST00000409195.6	c.472G>A	p.Glu158Lys	missense_variant	3/11	5	NM_152381.6
XIRP2-AS1	ENST00000525330.1	n.154+4830C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2346 AN: 152088 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00391

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0495

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0189 AC: 4687 AN: 247404 Hom.: 80 AF XY: 0.0214 AC XY: 2879 AN XY: 134296

Gnomad AFR exome AF: 0.00363

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.0000560

Gnomad SAS exome AF: 0.0480

Gnomad FIN exome AF: 0.00720

Gnomad NFE exome AF: 0.0209

Gnomad OTH exome AF: 0.0225

GnomAD4 exome AF: 0.0202 AC: 29534 AN: 1459734 Hom.: 437 Cov.: 30 AF XY: 0.0215 AC XY: 15646 AN XY: 726176

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.0119

Gnomad4 ASJ exome AF: 0.0156

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0490

Gnomad4 FIN exome AF: 0.00647

Gnomad4 NFE exome AF: 0.0203

Gnomad4 OTH exome AF: 0.0199

GnomAD4 genome AF: 0.0154 AC: 2344 AN: 152206 Hom.: 34 Cov.: 32 AF XY: 0.0149 AC XY: 1109 AN XY: 74404

Gnomad4 AFR AF: 0.00388

Gnomad4 AMR AF: 0.0168

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0491

Gnomad4 FIN AF: 0.00433

Gnomad4 NFE AF: 0.0217

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0204 Hom.: 63

Bravo AF: 0.0144

TwinsUK AF: 0.0200 AC: 74

ALSPAC AF: 0.0150 AC: 58

ESP6500AA AF: 0.00399 AC: 15

ESP6500EA AF: 0.0221 AC: 182

ExAC AF: 0.0200 AC: 2411

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.0228

EpiControl AF: 0.0253

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 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 -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Uncertain	0.99
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.80	T;T;T
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.71	N;N;N
REVEL	Benign	0.057
Sift	Benign	0.053	T;T;T
Sift4G	Benign	0.46	T;T;.
Polyphen		0.26	B;B;.
Vest4		0.17
MPC		0.023
ClinPred		0.00041	T
GERP RS		-0.12
gMVP		0.022

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: rs114147582; hg19: chr2-167992482;