NM_000053.4:c.2304delC
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000053.4(ATP7B):c.2304delC(p.Met769CysfsTer38) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as 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.2304delC | p.Met769CysfsTer38 | frameshift_variant | Exon 8 of 21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461892Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727248
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:6
This sequence change creates a premature translational stop signal (p.Met769Cysfs*38) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 9554743, 16603785). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 88957). For these reasons, this variant has been classified as Pathogenic. -
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This variant deletes 1 nucleotide in exon 8 of the ATP7B gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in over 10 individuals affected with autosomal recessive Wilson disease (PMID: 9554743, 23982005, 23159873, 31059521, 35782615), including three individuals in the homozygous state (PMID: 19118915) and three individuals in the compound heterozygous state with a second pathogenic ATP7B variant (PMID: 16603785, 25704634, 26799313). This variant has not been identified 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. -
Inborn genetic diseases Pathogenic:1
The c.2304delC pathogenic mutation, located in coding exon 8 of the ATP7B gene, results from a deletion of one nucleotide at nucleotide position 2304, causing a translational frameshift with a predicted alternate stop codon (p.M769Cfs*38). This mutation was first reported in an individual with Wilson disease; however, the second ATP7B alteration was not provided (Kim EK et al. Hum. Mutat., 1998;11:275-8). In a cohort of Chinese Han individuals with Wilson disease, this mutation was detected in conjunction with a second ATP7B alteration; however, the phase was not provided (Liu Y et al. Arch. Med. Res., 2015 Feb;46:164-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
not provided Pathogenic:1
ATP7B: PVS1, PP1:Strong, PM2, PM3, PP4 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at