13-51961831-A-G
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000053.4(ATP7B):c.1946+6T>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000031 in 1,612,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000053.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.1946+6T>C | splice_region_variant, intron_variant | Intron 6 of 20 | ENST00000242839.10 | NP_000044.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152080Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249578Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135406
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460596Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726684
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152080Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74286
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:6Uncertain:1
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Variant summary: The ATP7B c.1946+6T>C variant involves the alteration of a conserved intronic nucleotide. 3/5 splice prediction tools via Alamut suggest potential impact on a normal splicing pattern, which was confirmed by the RNA studies performed on RNA extracted from peripheral lymphoblasts and liver cells from a homozygous pt. Based on the results, c.1946+6T>C leads to an alternative transcript that is lacking exons 6,7,8 (Zappu_MCP_2012). The variant is present in the large control population dataset of ExAC at a very low frequency 0.0000084 (1/120708 chrs tested), which does not exceed the estimated maximal expected allele frequency of a pathogenic variant in ATP7B gene (0.0054). The variant of interest has been reported in affected individuals with clinically and biochemically confirmed dx of WD via published reports. Taken together, this variant is classified as Likely Pathogenic. -
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This sequence change falls in intron 6 of the ATP7B gene. It does not directly change the encoded amino acid sequence of the ATP7B protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Wilson disease (PMID: 22019423). ClinVar contains an entry for this variant (Variation ID: 495403). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exons 6-8, but is expected to preserve the integrity of the reading-frame (PMID: 22019423). For these reasons, this variant has been classified as Pathogenic. -
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This variant causes a T to C nucleotide substitution at the +6 position of intron 6 of the ATP7B gene. This variant has been observed in individuals affected with autosomal recessive Wilson disease (PMID: 22019423, 22677543, 34400371). One of these individuals has been reported to be homozygous for this variant (PMID: 22019423). An RNA study using cells derived from the homozygous individual has shown that the mutant allele does not lead to the production of full-length transcript but produces an aberrant transcript lacking exons 6, 7, and 8 (PMID: 22019423). This aberrant transcript has also been seen in heterozygous and wild-type samples (PMID: 7726170, 7833924, 9307043, 22019423) and is expected to result in an in-frame deletion of amino acid residues a.a. 624-785, which encode transmembrane domains of the ATP7B protein. A 3837 base-pair deletion that spans exon 6 through 8 was reported in an individual affected with Wilson disease who carried a second pathogenic variant in trans, c.3800A>C (p.Asp1267Ala) (PMID: 21707886). Many pathogenic missense substitution variants have been reported in the impacted region of the gene (ClinVar), indicating that the c.1946+6T>C variant disrupts a functionally important part of the ATP7B gene. This variant, c.1946+6T>C, has been identified in 1/249578 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:1
PP4, PM2, PM3, PS3, PS4_moderate -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at