12-110339638-T-C

Position:

• chr12-110339638-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The ENST00000539276.7(ATP2A2):​c.1678T>C​(p.Cys560Arg) 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: ATP2A2 ENST00000539276.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.97

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a strand (size 9) in uniprot entity AT2A2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000539276.7
• 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, 0.932
• PP5: Variant 12-110339638-T-C is Pathogenic according to our data. Variant chr12-110339638-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 17794.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-110339638-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP2A2	NM_170665.4	c.1678T>C	p.Cys560Arg	missense_variant	13/20	ENST00000539276.7	NP_733765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2A2	ENST00000539276.7	c.1678T>C	p.Cys560Arg	missense_variant	13/20	1	NM_170665.4	ENSP00000440045	P3
ATP2A2	ENST00000308664.10	c.1678T>C	p.Cys560Arg	missense_variant	13/21	1		ENSP00000311186	A1
ATP2A2	ENST00000548169.2	c.1351T>C	p.Cys451Arg	missense_variant	9/16	2		ENSP00000449454
ATP2A2	ENST00000377685.9	c.*1518T>C		3_prime_UTR_variant, NMD_transcript_variant	12/20	5		ENSP00000366913

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Keratosis follicularis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;D
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-12	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.68		Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);
MVP		0.98
MPC		2.7
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
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: rs121912734; hg19: chr12-110777443;