rs114147582

Variant names:

• chr2-167135972-G-A
• rs114147582
• NM_152381.6:c.472G>A

Variant summary

Our verdict is Benign. The variant received -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. 13/19 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
• Publications: 9 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 -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 VariationId is 403612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 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.472G>A	p.Glu158Lys	missense	Exon 3 of 11	NP_689594.4
	XIRP2	NM_001199143.2		c.472G>A	p.Glu158Lys	missense	Exon 3 of 11	NP_001186072.1	A4UGR9-6
	XIRP2	NM_001079810.4		c.472G>A	p.Glu158Lys	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.472G>A	p.Glu158Lys	missense	Exon 3 of 11	ENSP00000386840.2	A4UGR9-8
	XIRP2	ENST00000409728.5	TSL:1	c.472G>A	p.Glu158Lys	missense	Exon 3 of 11	ENSP00000386619.1	A4UGR9-6
	XIRP2	ENST00000409043.5	TSL:1	c.472G>A	p.Glu158Lys	missense	Exon 3 of 10	ENSP00000386454.1	A4UGR9-4

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

GnomAD2 exomes AF: 0.0189 AC: 4687 AN: 247404 AF XY: 0.0214

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 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

African (AFR) AF: 0.00272 AC: 91 AN: 33408

American (AMR) AF: 0.0119 AC: 528 AN: 44286

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 406 AN: 26054

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39584

South Asian (SAS) AF: 0.0490 AC: 4208 AN: 85946

European-Finnish (FIN) AF: 0.00647 AC: 345 AN: 53300

Middle Eastern (MID) AF: 0.0306 AC: 176 AN: 5760

European-Non Finnish (NFE) AF: 0.0203 AC: 22575 AN: 1111084

Other (OTH) AF: 0.0199 AC: 1200 AN: 60312

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

African (AFR) AF: 0.00388 AC: 161 AN: 41538

American (AMR) AF: 0.0168 AC: 257 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3466

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.0491 AC: 237 AN: 4826

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10614

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0217 AC: 1474 AN: 68002

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.0198 Hom.: 86

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
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
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.16
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.057
Sift	Benign	0.053	T
Sift4G	Benign	0.46	T
Polyphen		0.26	B
Vest4		0.17
MPC		0.023
ClinPred		0.00041	T
GERP RS		-0.12
PromoterAI		0.022	Neutral
gMVP		0.022
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: rs114147582; hg19: chr2-167992482;