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
Consequence
NM_000053.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.778dupC | p.Gln260ProfsTer10 | frameshift_variant | Exon 2 of 21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248652Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134894
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461804Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9AN XY: 727192
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74326
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:10Other:1
PVS1, PM2 -
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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. -
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. -
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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. -
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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
ATP7B: PVS1, PM3:Strong, PM2, PP4 -
PM2, PVS1 -
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at