rs1057517706
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1PP5_Very_StrongBS2
The NM_001378687.1(ATP2C1):βc.2375_2378delβ(p.Phe792SerfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,316 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.0000068 ( 0 hom. )
Consequence
ATP2C1
NM_001378687.1 frameshift
NM_001378687.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.01
Genes affected
ATP2C1 (HGNC:13211): (ATPase secretory pathway Ca2+ transporting 1) The protein encoded by this gene belongs to the family of P-type cation transport ATPases. This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the transport of calcium ions. Defects in this gene cause Hailey-Hailey disease, an autosomal dominant disorder. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 3-130997731-CTTTG-C is Pathogenic according to our data. Variant chr3-130997731-CTTTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 372308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-130997731-CTTTG-C is described in Lovd as [Pathogenic].
BS2
?
High AC in GnomAdExome4 at 10 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP2C1 | NM_001378687.1 | c.2375_2378del | p.Phe792SerfsTer10 | frameshift_variant | 25/28 | ENST00000510168.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP2C1 | ENST00000510168.6 | c.2375_2378del | p.Phe792SerfsTer10 | frameshift_variant | 25/28 | 5 | NM_001378687.1 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461316Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 726954
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GnomAD4 genome ? Cov.: 32
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32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial benign pemphigus Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 20, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2000 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 14, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 372308). This premature translational stop signal has been observed in individual(s) with Hailey-Hailey disease (PMID: 10615129, 25837627, 28035777, 29944739). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe792Serfs*10) in the ATP2C1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP2C1 are known to be pathogenic (PMID: 10615129, 10767338, 11841554). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 21, 2016 | The c.2375_2378delTTGT variant in the ATP2C1 gene has been reported previously in association with Hailey-Hailey disease (Hu et al., 2000). The deletion causes a frameshift starting with codon Phenylalanine 792, changes this amino acid to a Serine residue and creates a premature Stop codon at position 10 of the new reading frame, denoted p.Phe792SerfsX10. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, we interpret this variant as pathogenic. - |
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