rs1057517706

chr3-130997731-CTTTG-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001378687.1(ATP2C1):c.2375_2378del(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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ATP2C1 NM_001378687.1 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 16 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].

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

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461316 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 726954

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

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

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057517706; hg19: chr3-130716575;