chr3-130980591-T-C

Variant names:

• chr3-130980591-T-C
• rs137853015
• NM_001378687.1:c.1751T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001378687.1(ATP2C1):​c.1751T>C​(p.Leu584Pro) variant causes a missense change. 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: 7.15

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 3-130980591-T-C is Pathogenic according to our data. Variant chr3-130980591-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 5588.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-130980591-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2C1	NM_001378687.1	c.1751T>C	p.Leu584Pro	missense_variant	Exon 20 of 28	ENST00000510168.6	NP_001365616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2C1	ENST00000510168.6	c.1751T>C	p.Leu584Pro	missense_variant	Exon 20 of 28	5	NM_001378687.1	ENSP00000427461.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial benign pemphigus Pathogenic:1

Mar 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D;.;.;D;D;.;.;.;.;D;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;.;.;D;D;D;.;D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	4.1	.;.;.;H;H;H;.;.;H;H;H;H
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.5	.;.;.;D;D;.;D;D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;.;.;D;D;.;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;D;D;.;.;D;D;.;D
Vest4		0.96
MutPred		0.90		.;.;.;Loss of stability (P = 0.0077);Loss of stability (P = 0.0077);Loss of stability (P = 0.0077);.;.;Loss of stability (P = 0.0077);Loss of stability (P = 0.0077);Loss of stability (P = 0.0077);Loss of stability (P = 0.0077);
MVP		0.99
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs137853015; hg19: chr3-130699435;