3-130975387-G-T

Position:

• chr3-130975387-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_001378687.1(ATP2C1):​c.1469G>T​(p.Cys490Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP2C1 NM_001378687.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.28

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP2C1. . Trascript score misZ 3.7693 (greater than threshold 3.09). GenCC has associacion of gene with Hailey-Hailey disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 3-130975387-G-T is Pathogenic according to our data. Variant chr3-130975387-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 5586.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-130975387-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2C1	NM_001378687.1	c.1469G>T	p.Cys490Phe	missense_variant	18/28	ENST00000510168.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2C1	ENST00000510168.6	c.1469G>T	p.Cys490Phe	missense_variant	18/28	5	NM_001378687.1	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial benign pemphigus Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;.;.;D;D;.;.;.;.;D;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;.;.;D;D;D;.;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	4.0	.;.;.;H;H;H;.;.;H;H;H;H
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-10	.;.;.;D;D;.;D;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;.;.;D;D;.;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;D;D;.;.;D;D;.;D
Vest4		0.97
MutPred		0.87		.;.;.;Gain of MoRF binding (P = 0.0909);Gain of MoRF binding (P = 0.0909);Gain of MoRF binding (P = 0.0909);.;.;Gain of MoRF binding (P = 0.0909);Gain of MoRF binding (P = 0.0909);Gain of MoRF binding (P = 0.0909);Gain of MoRF binding (P = 0.0909);
MVP		0.98
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs137853014; hg19: chr3-130694231;