chr13-51949672-C-T

Position:

chr13-51949672-C-T

Variant summary

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

The ENST00000242839.10(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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

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

Exomes 𝑓: 0.58 ( 245981 hom. )

Consequence

ATP7B
ENST00000242839.10 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.25

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 topological_domain Extracellular (size 29) in uniprot entity ATP7B_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in ENST00000242839.10

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 id is 35708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51949672-C-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.2855G>A	p.Arg952Lys	missense_variant	12/21	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.2855G>A	p.Arg952Lys	missense_variant	12/21	1	NM_000053.4	ENSP00000242839	P1	P35670-1

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

GnomAD3 exomes

AF:

0.567

AC:

141220

AN:

249058

Hom.:

40568

AF XY:

0.566

AC XY:

76498

AN XY:

135216

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 SAS exome

AF:

0.522

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

Gnomad4 AFR exome

AF:

0.530

Gnomad4 AMR exome

AF:

0.633

Gnomad4 ASJ exome

AF:

0.574

Gnomad4 EAS exome

AF:

0.402

Gnomad4 SAS exome

AF:

0.521

Gnomad4 FIN exome

AF:

0.605

Gnomad4 NFE exome

AF:

0.587

Gnomad4 OTH exome

AF:

0.575

GnomAD4 genome

AF:

0.563

AC:

85608

AN:

152086

Hom.:

24237

Cov.:

AF XY:

0.563

AC XY:

41830

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.527

Gnomad4 AMR

AF:

0.597

Gnomad4 ASJ

AF:

0.568

Gnomad4 EAS

AF:

0.408

Gnomad4 SAS

AF:

0.523

Gnomad4 FIN

AF:

0.601

Gnomad4 NFE

AF:

0.586

Gnomad4 OTH

AF:

0.587

Alfa

AF:

0.579

Hom.:

62832

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

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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	Illumina Laboratory Services, Illumina	Jan 13, 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 03, 2024	- -

not specified

Benign:7

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, 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	Eurofins Ntd Llc (ga)	Apr 27, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
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	-	- -

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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: 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

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

0.051

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.18

CADD

Benign

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;.;.;.;.;.

MutationTaster

Benign

1.0

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

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

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

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