3-10359892-C-T

Variant names:

Variant summary

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

The NM_001001331.4(ATP2B2):c.1891G>A(p.Val631Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00943 in 1,614,226 control chromosomes in the GnomAD database, including 143 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0079 ( 17 hom., cov: 33)

Exomes 𝑓: 0.0096 ( 126 hom. )

Consequence

ATP2B2
NM_001001331.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.19

Publications

20 publications found

Variant links:

Genes affected

ATP2B2 (HGNC:815): (ATPase plasma membrane Ca2+ transporting 2) The protein encoded by this gene belongs to the family of P-type primary ion transport ATPases characterized by the formation of an aspartyl phosphate intermediate during the reaction cycle. These enzymes remove bivalent calcium ions from eukaryotic cells against very large concentration gradients and play a critical role in intracellular calcium homeostasis. The mammalian plasma membrane calcium ATPase isoforms are encoded by at least four separate genes and the diversity of these enzymes is further increased by alternative splicing of transcripts. The expression of different isoforms and splice variants is regulated in a developmental, tissue- and cell type-specific manner, suggesting that these pumps are functionally adapted to the physiological needs of particular cells and tissues. This gene encodes the plasma membrane calcium ATPase isoform 2. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ATP2B2 Gene-Disease associations (from GenCC):

hearing loss, autosomal dominant 82
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
autosomal recessive nonsyndromic hearing loss 12
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
neurodevelopmental disorder
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

ATP2B2 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=0.00996235).

BP6

Variant 3-10359892-C-T is Benign according to our data. Variant chr3-10359892-C-T is described in ClinVar as Benign. ClinVar VariationId is 17801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00788 (1200/152356) while in subpopulation AMR AF = 0.028 (428/15306). AF 95% confidence interval is 0.0258. There are 17 homozygotes in GnomAd4. There are 604 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1200 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2B2	NM_001001331.4 link	c.1891G>A	p.Val631Met	missense_variant	Exon 13 of 23	ENST00000360273.7	NP_001001331.1	Q01814-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2B2	ENST00000360273.7 link	c.1891G>A	p.Val631Met	missense_variant	Exon 13 of 23	5	NM_001001331.4	ENSP00000353414.2		Q01814-1

Frequencies

GnomAD3 genomes

AF:

0.00784

AC:

1193

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00289

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0274

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00883

Gnomad OTH

AF:

0.00716

GnomAD2 exomes

AF:

0.0115

AC:

2877

AN:

250766

AF XY:

0.0104

show subpopulations

Gnomad AFR exome

AF:

0.00252

Gnomad AMR exome

AF:

0.0477

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00171

Gnomad NFE exome

AF:

0.00840

Gnomad OTH exome

AF:

0.0103

GnomAD4 exome

AF:

0.00960

AC:

14027

AN:

1461870

Hom.:

126

Cov.:

AF XY:

0.00926

AC XY:

6731

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

33480

American (AMR)

AF:

0.0457

AC:

2043

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000306

AC:

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.00391

AC:

337

AN:

86256

European-Finnish (FIN)

AF:

0.00125

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00364

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00989

AC:

10999

AN:

1112004

Other (OTH)

AF:

0.00813

AC:

491

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

880

1761

2641

3522

4402

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

446

892

1338

1784

2230

<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:

0.00788

AC:

1200

AN:

152356

Hom.:

Cov.:

AF XY:

0.00811

AC XY:

604

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00289

AC:

120

AN:

41586

American (AMR)

AF:

0.0280

AC:

428

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00882

AC:

600

AN:

68030

Other (OTH)

AF:

0.00709

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

125

188

250

313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00804

Hom.:

Bravo

AF:

0.00967

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00721

AC:

ExAC

AF:

0.00881

AC:

1069

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00938

EpiControl

AF:

0.00717

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ATP2B2: BP1, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Agenesis of the corpus callosum with peripheral neuropathy

Benign:1

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Val586Met variant, sometimes called p.Val631Met due to a difference in cDNA numbering, in ATP2B2 has been identified in at least 5 individuals with hearing loss, including 3 siblings from 1 family (PMID: 15829536). Of note, 2 additional siblings in the same family did not have this variant and are less severely affected by disease. All 5 siblings were reported to be homozygous for a separate, causal variant in CDH23 (PMID: 15829536). This variant has also been identified in >4% of Latino chromosomes and 22 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Val586Met variant may have a mild impact on protein function (PMID: 22047666). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for autosomal recessive deafness but may modify disease. -

RECLASSIFIED - ATP2B2 POLYMORPHISM

Benign:1

Apr 14, 2005

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

ATP2B2-related disorder

Benign:1

Jun 20, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

.;T;.;.;.;.;.;.;T;.;.

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.89

.;D;.;D;D;D;D;D;.;D;D

MetaRNN

Benign

0.010

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Benign

1.6

.;L;.;.;.;.;.;.;L;.;.

PhyloP100

2.2

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.86

N;N;N;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.34

Sift

Benign

0.24

T;T;T;.;.;.;.;.;.;.;.

Sift4G

Benign

0.16

T;T;T;.;.;.;.;.;.;.;.

Polyphen

0.85

.;P;.;.;.;.;.;.;P;.;.

Vest4

0.40

MPC

1.8

ClinPred

0.012

GERP RS

4.9

Varity_R

0.17

gMVP

0.83

Mutation Taster

=78/22

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