13-51949672-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000053.4(ATP7B):c.2855G>A(p.Arg952Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 1,613,064 control chromosomes in the GnomAD database, including 270,218 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R952S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.56 ( 24237 hom., cov: 33)

Exomes 𝑓: 0.58 ( 245981 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:18

Conservation

PhyloP100: 2.25

Publications

93 publications found

Variant links:

Genes affected

ATP7B (HGNC:870): (ATPase copper transporting beta) This gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. This protein is a monomer, and functions as a copper-transporting ATPase which exports copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Mutations in this gene have been associated with Wilson disease which is characterized by copper accumulation. [provided by RefSeq, Dec 2019]

ATP7B Gene-Disease associations (from GenCC):

Wilson disease
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ATP7B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 198 curated pathogenic missense variants (we use a threshold of 10). The gene has 32 curated benign missense variants. Gene score misZ: -0.88091 (below the threshold of 3.09). Trascript score misZ: 0.82063 (below the threshold of 3.09). GenCC associations: The gene is linked to Wilson disease.

BP4

Computational evidence support a benign effect (MetaRNN=3.4731627E-4).

BP6

Variant 13-51949672-C-T is Benign according to our data. Variant chr13-51949672-C-T is described in ClinVar as Benign. ClinVar VariationId is 35708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4 link	c.2855G>A	p.Arg952Lys	missense_variant	Exon 12 of 21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 link	c.2855G>A	p.Arg952Lys	missense_variant	Exon 12 of 21	1	NM_000053.4	ENSP00000242839.5

Frequencies

GnomAD3 genomes

AF:

0.563

AC:

85554

AN:

151968

Hom.:

24228

Cov.:

show subpopulations

Gnomad AFR

AF:

0.527

Gnomad AMI

AF:

0.430

Gnomad AMR

AF:

0.597

Gnomad ASJ

AF:

0.568

Gnomad EAS

AF:

0.407

Gnomad SAS

AF:

0.523

Gnomad FIN

AF:

0.601

Gnomad MID

AF:

0.642

Gnomad NFE

AF:

0.586

Gnomad OTH

AF:

0.585

GnomAD2 exomes

AF:

0.567

AC:

141220

AN:

249058

AF XY:

0.566

show subpopulations

Gnomad AFR exome

AF:

0.521

Gnomad AMR exome

AF:

0.635

Gnomad ASJ exome

AF:

0.575

Gnomad EAS exome

AF:

0.396

Gnomad FIN exome

AF:

0.609

Gnomad NFE exome

AF:

0.582

Gnomad OTH exome

AF:

0.583

GnomAD4 exome

AF:

0.578

AC:

844929

AN:

1460978

Hom.:

245981

Cov.:

AF XY:

0.577

AC XY:

419281

AN XY:

726858

show subpopulations

African (AFR)

AF:

0.530

AC:

17725

AN:

33466

American (AMR)

AF:

0.633

AC:

28329

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.574

AC:

14987

AN:

26126

East Asian (EAS)

AF:

0.402

AC:

15938

AN:

39690

South Asian (SAS)

AF:

0.521

AC:

44969

AN:

86244

European-Finnish (FIN)

AF:

0.605

AC:

32121

AN:

53094

Middle Eastern (MID)

AF:

0.633

AC:

3649

AN:

5768

European-Non Finnish (NFE)

AF:

0.587

AC:

652489

AN:

1111506

Other (OTH)

AF:

0.575

AC:

34722

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

20298

40596

60894

81192

101490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17858

35716

53574

71432

89290

<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:

0.563

AC:

85608

AN:

152086

Hom.:

24237

Cov.:

AF XY:

0.563

AC XY:

41830

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.527

AC:

21850

AN:

41458

American (AMR)

AF:

0.597

AC:

9124

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.568

AC:

1972

AN:

3470

East Asian (EAS)

AF:

0.408

AC:

2107

AN:

5168

South Asian (SAS)

AF:

0.523

AC:

2518

AN:

4814

European-Finnish (FIN)

AF:

0.601

AC:

6366

AN:

10586

Middle Eastern (MID)

AF:

0.639

AC:

188

AN:

294

European-Non Finnish (NFE)

AF:

0.586

AC:

39853

AN:

67982

Other (OTH)

AF:

0.587

AC:

1239

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1956

3911

5867

7822

9778

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

732

1464

2196

2928

3660

<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:

0.575

Hom.:

89144

Bravo

AF:

0.563

TwinsUK

AF:

0.587

AC:

2177

ALSPAC

AF:

0.591

AC:

2276

ESP6500AA

AF:

0.521

AC:

1965

ESP6500EA

AF:

0.595

AC:

4896

ExAC

AF:

0.562

AC:

67900

Asia WGS

AF:

0.527

AC:

1827

AN:

3478

EpiCase

AF:

0.591

EpiControl

AF:

0.591

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Benign:9

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 03, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 08, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing;curation

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 05, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:7

Apr 27, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 05, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 64.047% in ExAC) based on the frequency threshold of 2.434% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease. -

Inborn genetic diseases

Benign:1

Jul 01, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Uncertain

0.45

T;T;.;.;.;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.016

T;T;T;T;T;T

MetaRNN

Benign

0.00035

T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.41

N;.;.;.;.;.

PhyloP100

2.2

PrimateAI

Benign

0.46

PROVEAN

Benign

1.2

N;N;N;N;.;N

REVEL

Uncertain

0.43

Sift

Benign

1.0

T;T;T;T;.;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.0

B;B;B;B;B;B

Vest4

0.043

MPC

0.060

ClinPred

0.0077

GERP RS

6.1

Varity_R

0.12

gMVP

0.59

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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