chr13-51974441-T-TG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000053.4(ATP7B):​c.778dupC​(p.Gln260ProfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 0.460
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-51974441-T-TG is Pathogenic according to our data. Variant chr13-51974441-T-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATP7BNM_000053.4 linkc.778dupC p.Gln260ProfsTer10 frameshift_variant Exon 2 of 21 ENST00000242839.10 NP_000044.2 P35670-1B7ZLR4A0A024RDX3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATP7BENST00000242839.10 linkc.778dupC p.Gln260ProfsTer10 frameshift_variant Exon 2 of 21 1 NM_000053.4 ENSP00000242839.5 P35670-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152146
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000402
AC:
1
AN:
248652
Hom.:
0
AF XY:
0.00000741
AC XY:
1
AN XY:
134894
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000889
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000109
AC:
16
AN:
1461804
Hom.:
0
Cov.:
33
AF XY:
0.0000124
AC XY:
9
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152146
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Wilson disease Pathogenic:10Other:1
Aug 23, 2023
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PVS1, PM2 -

Aug 10, 2021
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 21, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln260Profs*10) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). This variant is present in population databases (rs786204570, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 10980554, 11216666, 19172127, 20082719). This variant is also known as 777insC, 778insC, or 779insC. ClinVar contains an entry for this variant (Variation ID: 188938). For these reasons, this variant has been classified as Pathogenic. -

-
GenomeConnect, ClinGen
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

Variant interpretted as pathogenic and reported on 07/25/2018 by GTR ID PerkinElmer Genetics, Inc.. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

-
Genomics And Bioinformatics Analysis Resource, Columbia University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Sep 03, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 26, 2014
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: literature only

- -

Feb 14, 2017
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The ATP7B c.778dupC (p.Gln260Profs) variant results in a premature termination codon, predicted to cause a truncated or absent ATP7B protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as likely pathogenic/pathogenic by our laboratory (e.g. c.813delC (p.Cys271fs), c.845delT (p.Leu282fs), and c.1145_1151delCCCAACT (p.Ser382fs)). Mutation taster predicts a damaging outcome for this variant. This variant is absent in 120078 control chromosomes, while it was reported in multiple Wilson disease patients indicating pathogenicity. Moreover, HGMD lists several variants affecting the same codon indicating the variant to be located in a mutational hotspot and further supporting pathogenicity. One clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic. -

Nov 19, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 29, 2024
All of Us Research Program, National Institutes of Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 2 of the ATP7B gene, creating a frameshift and premature translation stop signal. This variant is also known as c.778insC and c.779insC in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with Wilson disease (PMID: 10980554, 11216666, 20082719, 23518715). Two of these individuals carried both ATP7B p.Lys175Serfs*28 and ATP7B p.Arg778Gly variants in combination with this variant (PMID: 27935710). This variant has been identified in 1/248652 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATP7B function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:3
Dec 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ATP7B: PVS1, PM3:Strong, PM2, PP4 -

Nov 08, 2021
Mayo Clinic Laboratories, Mayo Clinic
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM2, PVS1 -

Aug 04, 2021
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease This variant is associated with the following publications: (PMID: 10980554, 19172127, 11216666, 20082719) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

LitVar

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

Other links and lift over

dbSNP: rs786204570; hg19: chr13-52548577; API