rs121912736

Positions:

• chr12-110342435-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1 PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_170665.4(ATP2A2):​c.2305G>A​(p.Gly769Arg) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP2A2 NM_170665.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PS1: Transcript NM_170665.4 (ATP2A2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a helix (size 40) in uniprot entity AT2A2_HUMAN there are 23 pathogenic changes around while only 0 benign (100%) in NM_170665.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP2A2. . Gene score misZ 4.8777 (greater than the threshold 3.09). Trascript score misZ 7.0223 (greater than threshold 3.09). GenCC has associacion of gene with acrokeratosis verruciformis, Darier disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 12-110342435-G-A is Pathogenic according to our data. Variant chr12-110342435-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17798.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-110342435-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP2A2	NM_170665.4	c.2305G>A	p.Gly769Arg	missense_variant	15/20	ENST00000539276.7	NP_733765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2A2	ENST00000539276.7	c.2305G>A	p.Gly769Arg	missense_variant	15/20	1	NM_170665.4	ENSP00000440045	P3
ATP2A2	ENST00000308664.10	c.2305G>A	p.Gly769Arg	missense_variant	15/21	1		ENSP00000311186	A1
ATP2A2	ENST00000548169.2	c.1978G>A	p.Gly660Arg	missense_variant	11/16	2		ENSP00000449454
ATP2A2	ENST00000377685.9	c.*2145G>A		3_prime_UTR_variant, NMD_transcript_variant	14/20	5		ENSP00000366913

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Darier disease, segmental Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2000

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 07, 2019

Published functional studies demonstrate protein expression level was higher than 30% of wild type, but the variant completely abolished Ca2+-ATPase activity and Ca2+ transport activity, resulting in severe disruption of Ca2+ homeostasis (Miyauchi et al., 2006); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28035777, 11121153, 16766529, 22035154) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	.;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	-0.0049	T
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.77		Gain of catalytic residue at G769 (P = 0.0057);Gain of catalytic residue at G769 (P = 0.0057);
MVP		1.0
MPC		2.9
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		1.0

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: rs121912736; hg19: chr12-110780240;