chr13-51958492-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1PP2BP4_StrongBP6

The NM_000053.4(ATP7B):c.2174G>A(p.Arg725Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,614,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R725W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: -0.434

Publications

4 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: Likely_benign. The variant received -2 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, 12 uncertain in NM_000053.4

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=0.009857595).

BP6

Variant 13-51958492-C-T is Benign according to our data. Variant chr13-51958492-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 456551.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4 link	c.2174G>A	p.Arg725Lys	missense_variant	Exon 8 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.2174G>A	p.Arg725Lys	missense_variant	Exon 8 of 21	1	NM_000053.4	ENSP00000242839.5		P35670-1

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00268

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000144

AC:

AN:

249556

AF XY:

0.000111

show subpopulations

Gnomad AFR exome

AF:

0.00232

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000643

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00254

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112012

Other (OTH)

AF:

0.0000828

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000735

AC:

112

AN:

152328

Hom.:

Cov.:

AF XY:

0.000671

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00267

AC:

111

AN:

41564

American (AMR)

AF:

0.0000654

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000386

Hom.:

Bravo

AF:

0.000695

ESP6500AA

AF:

0.00143

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000173

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Wilson disease

Uncertain:2Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 20, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ATP7B c.2174G>A; p.Arg725Lys variant (rs115227204), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 456551). This variant is found in the African/African-American population with an allele frequency of 0.3% (63/24202 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.158). Due to limited information, the clinical significance of this variant is uncertain at this time. -

Dec 19, 2022

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with lysine at codon 725 of the ATP7B protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with Wilson disease in the literature. This variant has been identified in 63/280952 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Dec 02, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

8.3

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.39

T;.;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.65

T;T;T

M_CAP

Benign

0.042

MetaRNN

Benign

0.0099

T;T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

0.45

N;.;.

PhyloP100

-0.43

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.65

N;N;N

REVEL

Benign

0.16

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;P;B

Vest4

0.21

MVP

0.76

MPC

0.060

ClinPred

0.0066

GERP RS

0.18

Varity_R

0.060

gMVP

0.65

Mutation Taster

=71/29

polymorphism

(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