13-51970669-C-G

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.1366G>C(p.Val456Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 1,613,902 control chromosomes in the GnomAD database, including 178,885 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. V456V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.41 ( 13491 hom., cov: 32)

Exomes 𝑓: 0.47 ( 165394 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.911

Publications

69 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=1.083074E-4).

BP6

Variant 13-51970669-C-G is Benign according to our data. Variant chr13-51970669-C-G is described in ClinVar as Benign. ClinVar VariationId is 35702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4 link	c.1366G>C	p.Val456Leu	missense_variant	Exon 3 of 21	ENST00000242839.10	NP_000044.2	P35670-1B7ZLR4A0A024RDX3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 link	c.1366G>C	p.Val456Leu	missense_variant	Exon 3 of 21	1	NM_000053.4	ENSP00000242839.5		P35670-1

Frequencies

GnomAD3 genomes

AF:

0.407

AC:

61848

AN:

151970

Hom.:

13493

Cov.:

show subpopulations

Gnomad AFR

AF:

0.233

Gnomad AMI

AF:

0.376

Gnomad AMR

AF:

0.410

Gnomad ASJ

AF:

0.430

Gnomad EAS

AF:

0.487

Gnomad SAS

AF:

0.353

Gnomad FIN

AF:

0.528

Gnomad MID

AF:

0.487

Gnomad NFE

AF:

0.488

Gnomad OTH

AF:

0.464

GnomAD2 exomes

AF:

0.440

AC:

109640

AN:

249182

AF XY:

0.441

show subpopulations

Gnomad AFR exome

AF:

0.226

Gnomad AMR exome

AF:

0.388

Gnomad ASJ exome

AF:

0.436

Gnomad EAS exome

AF:

0.483

Gnomad FIN exome

AF:

0.537

Gnomad NFE exome

AF:

0.484

Gnomad OTH exome

AF:

0.472

GnomAD4 exome

AF:

0.472

AC:

689334

AN:

1461814

Hom.:

165394

Cov.:

AF XY:

0.469

AC XY:

341034

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.228

AC:

7632

AN:

33480

American (AMR)

AF:

0.393

AC:

17569

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.433

AC:

11312

AN:

26132

East Asian (EAS)

AF:

0.476

AC:

18906

AN:

39700

South Asian (SAS)

AF:

0.344

AC:

29708

AN:

86258

European-Finnish (FIN)

AF:

0.527

AC:

28135

AN:

53412

Middle Eastern (MID)

AF:

0.465

AC:

2685

AN:

5768

European-Non Finnish (NFE)

AF:

0.490

AC:

545191

AN:

1111946

Other (OTH)

AF:

0.467

AC:

28196

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

22040

44080

66120

88160

110200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15800

31600

47400

63200

79000

<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:

0.407

AC:

61856

AN:

152088

Hom.:

13491

Cov.:

AF XY:

0.409

AC XY:

30433

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.232

AC:

9647

AN:

41498

American (AMR)

AF:

0.409

AC:

6256

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.430

AC:

1491

AN:

3466

East Asian (EAS)

AF:

0.487

AC:

2521

AN:

5178

South Asian (SAS)

AF:

0.353

AC:

1704

AN:

4822

European-Finnish (FIN)

AF:

0.528

AC:

5583

AN:

10568

Middle Eastern (MID)

AF:

0.493

AC:

145

AN:

294

European-Non Finnish (NFE)

AF:

0.488

AC:

33191

AN:

67964

Other (OTH)

AF:

0.463

AC:

976

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1813

3626

5438

7251

9064

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

584

1168

1752

2336

2920

<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:

0.430

Hom.:

4418

Bravo

AF:

0.393

TwinsUK

AF:

0.490

AC:

1818

ALSPAC

AF:

0.496

AC:

1913

ESP6500AA

AF:

0.224

AC:

887

ESP6500EA

AF:

0.492

AC:

4068

ExAC

AF:

0.434

AC:

52469

Asia WGS

AF:

0.423

AC:

1466

AN:

3478

EpiCase

AF:

0.488

EpiControl

AF:

0.486

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Apr 27, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 08, 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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Wilson disease

Benign:8

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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. -

Oct 03, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Nov 26, 2011

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

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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

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: 53.754% 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

Aug 02, 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

0.075

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.32

CADD

Benign

5.0

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.28

T;T;.;.;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.56

T;T;T;T;T;T

MetaRNN

Benign

0.00011

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;.;N;.;.;.

PhyloP100

-0.91

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.18

N;N;N;N;.;N

REVEL

Benign

0.12

Sift

Benign

0.60

T;T;T;T;.;T

Sift4G

Benign

0.63

T;T;T;T;T;T

Polyphen

0.0010

B;B;B;B;B;B

Vest4

0.037

MutPred

0.10

Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);.;Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);

MPC

0.058

ClinPred

0.0082

GERP RS

-0.18

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.078

gMVP

0.28

Mutation Taster

=80/20

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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