2-166903492-A-G

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.10A>G(p.Met4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00276 in 1,612,416 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (63 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (37 hom.)
• Consequence: XIRP2 NM_152381.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.02

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036630034).
• BP6: Variant 2-166903492-A-G is Benign according to our data. Variant chr2-166903492-A-G is described in ClinVar as [Benign]. Clinvar id is 791155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0144 (2198/152194) while in subpopulation AFR AF= 0.0501 (2080/41538). AF 95% confidence interval is 0.0483. There are 63 homozygotes in gnomad4. There are 1025 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 63 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XIRP2	NM_152381.6	c.10A>G	p.Met4Val	missense_variant	2/11	ENST00000409195.6
XIRP2	NM_001199143.2	c.10A>G	p.Met4Val	missense_variant	2/11
XIRP2	NM_001079810.4	c.10A>G	p.Met4Val	missense_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XIRP2	ENST00000409195.6	c.10A>G	p.Met4Val	missense_variant	2/11	5	NM_152381.6
XIRP2	ENST00000409728.5	c.10A>G	p.Met4Val	missense_variant	2/11	1
XIRP2	ENST00000409043.5	c.10A>G	p.Met4Val	missense_variant	2/10	1
XIRP2	ENST00000672716.1	c.34A>G	p.Met12Val	missense_variant	2/10

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2192 AN: 152076 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0501

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00386 AC: 956 AN: 247712 Hom.: 20 AF XY: 0.00275 AC XY: 370 AN XY: 134334

Gnomad AFR exome AF: 0.0530

Gnomad AMR exome AF: 0.00204

Gnomad ASJ exome AF: 0.00343

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000196

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.00154 AC: 2252 AN: 1460222 Hom.: 37 Cov.: 33 AF XY: 0.00130 AC XY: 947 AN XY: 726338

Gnomad4 AFR exome AF: 0.0508

Gnomad4 AMR exome AF: 0.00258

Gnomad4 ASJ exome AF: 0.00269

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000697

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.00328

GnomAD4 genome AF: 0.0144 AC: 2198 AN: 152194 Hom.: 63 Cov.: 32 AF XY: 0.0138 AC XY: 1025 AN XY: 74414

Gnomad4 AFR AF: 0.0501

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00280 Hom.: 19

Bravo AF: 0.0166

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0476 AC: 181

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00485 AC: 586

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000437

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

XIRP2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 24, 2019

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	19
Dann	Benign	0.97
Eigen	Benign	-0.050
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.58	T;T;T
MetaRNN	Benign	0.0037	T;T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	0.99	N;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.82	N;N;N
REVEL	Benign	0.056
Sift	Uncertain	0.0050	D;D;D
Sift4G	Benign	0.13	T;T;.
Polyphen		0.037	B;B;.
Vest4		0.20
MVP		0.29
MPC		0.020
ClinPred		0.031	T
GERP RS		5.3
gMVP		0.017

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: rs80326955; hg19: chr2-167760002;