NM_152381.6:c.519T>G

Variant names:

• chr2-167136019-T-G
• rs546765780
• NM_152381.6:c.519T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_152381.6(XIRP2):​c.519T>G​(p.Phe173Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,611,146 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (1 hom.)
• Consequence: XIRP2 NM_152381.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.80
• Publications: 0 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]

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02515611).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152381.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIRP2	NM_152381.6	MANE Select	c.519T>G	p.Phe173Leu	missense	Exon 3 of 11	NP_689594.4
	XIRP2	NM_001199143.2		c.519T>G	p.Phe173Leu	missense	Exon 3 of 11	NP_001186072.1	A4UGR9-6
	XIRP2	NM_001079810.4		c.519T>G	p.Phe173Leu	missense	Exon 3 of 10	NP_001073278.1	A4UGR9-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIRP2	ENST00000409195.6	TSL:5 MANE Select	c.519T>G	p.Phe173Leu	missense	Exon 3 of 11	ENSP00000386840.2	A4UGR9-8
	XIRP2	ENST00000409728.5	TSL:1	c.519T>G	p.Phe173Leu	missense	Exon 3 of 11	ENSP00000386619.1	A4UGR9-6
	XIRP2	ENST00000409043.5	TSL:1	c.519T>G	p.Phe173Leu	missense	Exon 3 of 10	ENSP00000386454.1	A4UGR9-4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000406 AC: 10 AN: 246508 AF XY: 0.0000448

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1458856 Hom.: 1 Cov.: 30 AF XY: 0.0000234 AC XY: 17 AN XY: 725782

African (AFR) AF: 0.00 AC: 0 AN: 33370

American (AMR) AF: 0.00 AC: 0 AN: 43992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.000256 AC: 22 AN: 85894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53198

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110784

Other (OTH) AF: 0.0000166 AC: 1 AN: 60284

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74468

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000579 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Benign	0.78
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.91	T
PhyloP100		3.8
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.073
Sift	Benign	0.31	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.14		Loss of methylation at K169 (P = 0.0787)
MVP		0.13
MPC		0.020
ClinPred		0.015	T
GERP RS		3.1
PromoterAI		0.054	Neutral
gMVP		0.018
Mutation Taster		=84/16	polymorphism

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: rs546765780; hg19: chr2-167992529;