chr2-167135961-G-A

Variant names:

• chr2-167135961-G-A
• rs368577607
• NM_152381.6:c.461G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_152381.6(XIRP2):​c.461G>A​(p.Gly154Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000306 in 1,610,900 control chromosomes in the GnomAD database, including 8 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 Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (8 hom.)
• Consequence: XIRP2 NM_152381.6 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.72
• Publications: 1 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040955544).
• BP6: Variant 2-167135961-G-A is Benign according to our data. Variant chr2-167135961-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3049522.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

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.461G>A	p.Gly154Glu	missense	Exon 3 of 11	NP_689594.4
	XIRP2	NM_001199143.2		c.461G>A	p.Gly154Glu	missense	Exon 3 of 11	NP_001186072.1	A4UGR9-6
	XIRP2	NM_001079810.4		c.461G>A	p.Gly154Glu	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.461G>A	p.Gly154Glu	missense	Exon 3 of 11	ENSP00000386840.2	A4UGR9-8
	XIRP2	ENST00000409728.5	TSL:1	c.461G>A	p.Gly154Glu	missense	Exon 3 of 11	ENSP00000386619.1	A4UGR9-6
	XIRP2	ENST00000409043.5	TSL:1	c.461G>A	p.Gly154Glu	missense	Exon 3 of 10	ENSP00000386454.1	A4UGR9-4

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 151938 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000750 AC: 185 AN: 246538 AF XY: 0.00103

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: 0.00000893

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000320 AC: 467 AN: 1458844 Hom.: 8 Cov.: 30 AF XY: 0.000482 AC XY: 350 AN XY: 725764

African (AFR) AF: 0.00 AC: 0 AN: 33350

American (AMR) AF: 0.00 AC: 0 AN: 44034

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39516

South Asian (SAS) AF: 0.00520 AC: 447 AN: 85904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1110748

Other (OTH) AF: 0.000232 AC: 14 AN: 60254

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152056 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74332

African (AFR) AF: 0.0000241 AC: 1 AN: 41544

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00519 AC: 25 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67882

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.0000258 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.000894 AC: 108

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	XIRP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	9.0
DANN	Uncertain	0.99
Eigen	Benign	-0.040
Eigen_PC	Benign	-0.012
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.44	T
PhyloP100		1.7
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.095
Sift	Benign	0.061	T
Sift4G	Benign	0.13	T
Polyphen		0.62	P
Vest4		0.22
MutPred		0.14		Gain of solvent accessibility (P = 0.024)
MVP		0.46
MPC		0.021
ClinPred		0.095	T
GERP RS		4.6
PromoterAI		0.030	Neutral
gMVP		0.014
Mutation Taster		=88/12	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: rs368577607; hg19: chr2-167992471; COSMIC: COSV107330360;