chr2-167135972-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.164

Publications

9 publications found

Variant links:

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 links:

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

XIRP2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIRP2	NM_152381.6 link	c.472G>A	p.Glu158Lys	missense_variant	Exon 3 of 11	ENST00000409195.6	NP_689594.4	A4UGR9-8
XIRP2	NM_001199143.2 link	c.472G>A	p.Glu158Lys	missense_variant	Exon 3 of 11		NP_001186072.1	A4UGR9-6
XIRP2	NM_001079810.4 link	c.472G>A	p.Glu158Lys	missense_variant	Exon 3 of 10		NP_001073278.1	A4UGR9-4
XIRP2-AS1	NR_046665.1 link	n.154+4830C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XIRP2	ENST00000409195.6 link	c.472G>A	p.Glu158Lys	missense_variant	Exon 3 of 11	5	NM_152381.6	ENSP00000386840.2		A4UGR9-8

Frequencies

GnomAD3 genomes

AF:

0.0154

AC:

2346

AN:

152088

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0215

AC XY:

15646

AN XY:

726176

show subpopulations

African (AFR)

AF:

0.00272

AC:

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

1386

2772

4157

5543

6929

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

812

1624

2436

3248

4060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0154

AC:

2344

AN:

152206

Hom.:

Cov.:

AF XY:

0.0149

AC XY:

1109

AN XY:

74404

show subpopulations

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:

AN:

3466

East Asian (EAS)

AF:

0.000387

AC:

AN:

5172

South Asian (SAS)

AF:

0.0491

AC:

237

AN:

4826

European-Finnish (FIN)

AF:

0.00433

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0217

AC:

1474

AN:

68002

Other (OTH)

AF:

0.0128

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

123

245

368

490

613

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0198

Hom.:

Bravo

AF:

0.0144

TwinsUK

AF:

0.0200

AC:

ALSPAC

AF:

0.0150

AC:

ESP6500AA

AF:

0.00399

AC:

ESP6500EA

AF:

0.0221

AC:

182

ExAC

AF:

0.0200

AC:

2411

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0228

EpiControl

AF:

0.0253

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.80

T;T;T

MetaRNN

Benign

0.0016

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

0.16

PrimateAI

Benign

0.25

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

GERP RS

-0.12

PromoterAI

0.022

Neutral

(source)

gMVP

0.022

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over