chr13-51950352-T-C

Position:

chr13-51950352-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The ENST00000242839.10(ATP7B):c.2495A>G(p.Lys832Arg) variant causes a missense change. The variant allele was found at a frequency of 0.562 in 1,613,790 control chromosomes in the GnomAD database, including 256,999 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K832T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.54 ( 22333 hom., cov: 31)

Exomes 𝑓: 0.56 ( 234666 hom. )

Consequence

ATP7B
ENST00000242839.10 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:20

Conservation

PhyloP100: 6.19

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000242839.10

BP4

Computational evidence support a benign effect (MetaRNN=0.0037171245).

BP6

Variant 13-51950352-T-C is Benign according to our data. Variant chr13-51950352-T-C is described in ClinVar as [Benign]. Clinvar id is 35707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51950352-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.2495A>G	p.Lys832Arg	missense_variant	10/21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 linkuse as main transcript	c.2495A>G	p.Lys832Arg	missense_variant	10/21	1	NM_000053.4	ENSP00000242839	P1	P35670-1

Frequencies

GnomAD3 genomes

AF:

0.540

AC:

81944

AN:

151884

Hom.:

22328

Cov.:

show subpopulations

Gnomad AFR

AF:

0.493

Gnomad AMI

AF:

0.404

Gnomad AMR

AF:

0.507

Gnomad ASJ

AF:

0.565

Gnomad EAS

AF:

0.404

Gnomad SAS

AF:

0.514

Gnomad FIN

AF:

0.599

Gnomad MID

AF:

0.630

Gnomad NFE

AF:

0.577

Gnomad OTH

AF:

0.565

GnomAD3 exomes

AF:

0.539

AC:

134395

AN:

249370

Hom.:

36684

AF XY:

0.542

AC XY:

73388

AN XY:

135292

show subpopulations

Gnomad AFR exome

AF:

0.486

Gnomad AMR exome

AF:

0.491

Gnomad ASJ exome

AF:

0.570

Gnomad EAS exome

AF:

0.396

Gnomad SAS exome

AF:

0.510

Gnomad FIN exome

AF:

0.607

Gnomad NFE exome

AF:

0.574

Gnomad OTH exome

AF:

0.563

GnomAD4 exome

AF:

0.565

AC:

825260

AN:

1461788

Hom.:

234666

Cov.:

AF XY:

0.564

AC XY:

409857

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.495

Gnomad4 AMR exome

AF:

0.496

Gnomad4 ASJ exome

AF:

0.569

Gnomad4 EAS exome

AF:

0.401

Gnomad4 SAS exome

AF:

0.509

Gnomad4 FIN exome

AF:

0.602

Gnomad4 NFE exome

AF:

0.578

Gnomad4 OTH exome

AF:

0.561

GnomAD4 genome

AF:

0.539

AC:

81991

AN:

152002

Hom.:

22333

Cov.:

AF XY:

0.538

AC XY:

39989

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.493

Gnomad4 AMR

AF:

0.507

Gnomad4 ASJ

AF:

0.565

Gnomad4 EAS

AF:

0.405

Gnomad4 SAS

AF:

0.515

Gnomad4 FIN

AF:

0.599

Gnomad4 NFE

AF:

0.577

Gnomad4 OTH

AF:

0.566

Alfa

AF:

0.563

Hom.:

58409

Bravo

AF:

0.532

TwinsUK

AF:

0.575

AC:

2132

ALSPAC

AF:

0.582

AC:

2242

ESP6500AA

AF:

0.484

AC:

2050

ESP6500EA

AF:

0.586

AC:

4978

ExAC

AF:

0.537

AC:

65059

Asia WGS

AF:

0.504

AC:

1750

AN:

3478

EpiCase

AF:

0.583

EpiControl

AF:

0.582

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Benign:11

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 03, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 08, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone, for Wilson disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 27, 2016	- -

not provided

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 60.857% 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.10 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 01, 2016

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

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

D;D;.;.;.;.

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.81

T;T;T;T;T;T

MetaRNN

Benign

0.0037

T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.41

N;.;.;.;.;.

MutationTaster

Benign

0.000019

P;P;P;P;P;P;P

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.0

N;N;N;N;.;N

REVEL

Uncertain

0.47

Sift

Benign

0.087

T;T;T;T;.;T

Sift4G

Benign

0.12

T;T;T;T;T;T

Polyphen

0.42

B;B;P;B;P;P

Vest4

0.34

MPC

0.087

ClinPred

0.0087

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over