12-110281790-A-T

Position:

• chr12-110281790-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_170665.4(ATP2A2):​c.1A>T​(p.Met1?) variant causes a initiator codon 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP2A2 NM_170665.4 initiator_codon
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.59

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 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_170665.4 (ATP2A2) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-110281790-A-T is Pathogenic according to our data. Variant chr12-110281790-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 280505.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-110281790-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP2A2	NM_170665.4	c.1A>T	p.Met1?	initiator_codon_variant	1/20	ENST00000539276.7	NP_733765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2A2	ENST00000539276.7	c.1A>T	p.Met1?	initiator_codon_variant	1/20	1	NM_170665.4	ENSP00000440045.2
ATP2A2	ENST00000308664.10	c.1A>T	p.Met1?	initiator_codon_variant	1/21	1		ENSP00000311186.6
ATP2A2	ENST00000552636.2	c.-257-814A>T		intron_variant		4		ENSP00000447406.2
ATP2A2	ENST00000377685.9	n.1A>T		non_coding_transcript_exon_variant	1/20	5		ENSP00000366913.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 21, 2016

The c.1 A>T pathogenic variant in the ATP2A2 gene alters the initiator Methionine codon, and the resultant protein would be described as p.Met1? using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met. In addition, the c.1 A>T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project." -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Uncertain	0.50	.;D
Eigen	Benign	0.042
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.15	D
PROVEAN	Benign	-2.0	N;N
REVEL	Pathogenic	0.75
Sift	Benign	0.037	D;D
Sift4G	Benign	0.11	T;T
Polyphen		0.075	B;B
Vest4		0.78
MutPred		0.75		Gain of catalytic residue at N3 (P = 0.1757);Gain of catalytic residue at N3 (P = 0.1757);
MVP		1.0
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.56
gMVP		0.53

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: rs886041697; hg19: chr12-110719595;