rs121912738

Variant names:

• chr12-110296666-G-A
• rs121912738
• NM_170665.4:c.392G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-110296666-G-A
• chr12-110296666-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_170665.4(ATP2A2):​c.392G>A​(p.Arg131Gln) 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. 10/17 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R131L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATP2A2 NM_170665.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:4
• Conservation: PhyloP100: 9.59
• Publications: 7 publications found

Genes affected

ATP2A2 (HGNC:812): (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2) This gene encodes one of the SERCA Ca(2+)-ATPases, which are intracellular pumps located in the sarcoplasmic or endoplasmic reticula of the skeletal muscle. This enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol into the sarcoplasmic reticulum lumen, and is involved in regulation of the contraction/relaxation cycle. Mutations in this gene cause Darier-White disease, also known as keratosis follicularis, an autosomal dominant skin disorder characterized by loss of adhesion between epidermal cells and abnormal keratinization. Other types of mutations in this gene have been associated with various forms of muscular dystrophies. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2019]

ATP2A2 Gene-Disease associations (from GenCC):

• acrokeratosis verruciformis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Darier disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Illumina

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ATP2A2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 28 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 4.8777 (above the threshold of 3.09). Trascript score misZ: 7.0223 (above the threshold of 3.09). GenCC associations: The gene is linked to acrokeratosis verruciformis, Darier disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866
• PP5: Variant 12-110296666-G-A is Pathogenic according to our data. Variant chr12-110296666-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 17800.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2A2	NM_170665.4	c.392G>A	p.Arg131Gln	missense_variant	Exon 5 of 20	ENST00000539276.7	NP_733765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2A2	ENST00000539276.7	c.392G>A	p.Arg131Gln	missense_variant	Exon 5 of 20	1	NM_170665.4	ENSP00000440045.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:3

Dec 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 131 of the ATP2A2 protein (p.Arg131Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Darier disease (PMID: 10441323, 11168576, 12072062, 28035777). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17800). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP2A2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATP2A2 function (PMID: 16766529). For these reasons, this variant has been classified as Pathogenic. -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Keratosis follicularis Pathogenic:1

Jun 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		9.6
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.63
Vest4		0.77
MutPred		0.20		Gain of catalytic residue at R35 (P = 0.002);
MVP		0.82
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.94
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121912738; hg19: chr12-110734471;