rs121912734

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5

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

Scores

13
5
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.97
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
ATP2A2NM_170665.4 linkuse as main transcriptc.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
ATP2A2ENST00000539276.7 linkuse as main transcriptc.1678T>C p.Cys560Arg missense_variant 13/201 NM_170665.4 ENSP00000440045 P3P16615-1
ATP2A2ENST00000308664.10 linkuse as main transcriptc.1678T>C p.Cys560Arg missense_variant 13/211 ENSP00000311186 A1P16615-2
ATP2A2ENST00000548169.2 linkuse as main transcriptc.1351T>C p.Cys451Arg missense_variant 9/162 ENSP00000449454
ATP2A2ENST00000377685.9 linkuse as main transcriptc.*1518T>C 3_prime_UTR_variant, NMD_transcript_variant 12/205 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
LINK: link

Submissions by phenotype

Keratosis follicularis Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121912734; hg19: chr12-110777443; API