chr13-51950303-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_000053.4(ATP7B):c.2544C>T(p.Gly848Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000631 in 1,614,126 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00065 ( 1 hom. )
Consequence
ATP7B
NM_000053.4 synonymous
NM_000053.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.389
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 13-51950303-G-A is Benign according to our data. Variant chr13-51950303-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 312387.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=3}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATP7B | NM_000053.4 | c.2544C>T | p.Gly848Gly | synonymous_variant | 10/21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
Frequencies
GnomAD3 genomes 0.000460 AC: 70AN: 152126Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000597 AC: 149AN: 249530Hom.: 0 AF XY: 0.000613 AC XY: 83AN XY: 135390
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GnomAD4 exome AF: 0.000649 AC: 949AN: 1461882Hom.: 1 Cov.: 35 AF XY: 0.000650 AC XY: 473AN XY: 727244
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GnomAD4 genome 0.000460 AC: 70AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22AN XY: 74444
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Wilson disease Uncertain:3Benign:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 30, 2019 | The ATP7B c.2544C>T; p.Gly848Gly variant (rs200996053), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 312387). This variant is found in the Finnish European population with an overall allele frequency of 0.10% (26/25026 alleles) in the Genome Aggregation Database. This is a synonymous variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic splice donor site, though mRNA studies would be required to confirm this. Due to limited information, the clinical significance of the p.Gly848Gly variant is uncertain at this time. - |
| Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This synonymous variant causes a C to T nucleotide change in exon #10 of the ATP7B gene. Splice site prediction tools indicate that this variant may activate a cryptic splice donor site 33 nucleotides upstream of the native intron 10 splice donor site. 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 166/280920 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:5
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 20, 2024 | Identified without a second ATP7B variant in a patient with dystonia in the published literature, however, this individual harbored variants in additional genes that are more likely to be contributing to this phenotype (PMID: 34395002); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 34395002) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 14, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
ATP7B-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 20, 2024 | The ATP7B c.2544C>T variant is not predicted to result in an amino acid change (p.=). This variant is predicted to impact splicing at the donor splice site; however, this is based on computational modeling and this variant has not been functionally validated (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.10% of alleles in individuals of European (Finnish) descent in gnomAD, which may be too common to be a primary cause of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Details are displayed if max score is > 0.2
DS_DG_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at