rs786204570
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000053.4(ATP7B):βc.778_779insCβ(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 (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000020 ( 0 hom., cov: 33)
Exomes π: 0.000011 ( 0 hom. )
Consequence
ATP7B
NM_000053.4 frameshift
NM_000053.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.460
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
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Very rare variant in population databases, with high coverage;
PP5
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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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.778_779insC | p.Gln260ProfsTer10 | frameshift_variant | 2/21 | ENST00000242839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.778_779insC | p.Gln260ProfsTer10 | frameshift_variant | 2/21 | 1 | NM_000053.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248652Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134894
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GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461804Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9AN XY: 727192
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74326
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Wilson disease Pathogenic:9Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | 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. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Aug 26, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 19, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 19, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Aug 23, 2023 | PVS1, PM2 - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 14, 2017 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 03, 2021 | - - |
Pathogenic, no assertion criteria provided | research | Genomics And Bioinformatics Analysis Resource, Columbia University | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 21, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 04, 2021 | 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) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 08, 2021 | PM2, PVS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | ATP7B: PVS1, PM2, PM3 - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at