chr12-110281790-A-G

Position:

• chr12-110281790-A-G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_170665.4(ATP2A2):​c.1A>G​(p.Met1?) variant causes a start lost 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATP2A2 NM_170665.4 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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 20 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 ClinVar as 280505
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-110281790-A-G is Pathogenic according to our data. Variant chr12-110281790-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1693414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-110281790-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2A2	ENST00000539276.7	c.1A>G	p.Met1?	start_lost	1/20	1	NM_170665.4	P3
ATP2A2	ENST00000308664.10	c.1A>G	p.Met1?	start_lost	1/21	1		A1
ATP2A2	ENST00000552636.2	c.-257-814A>G		intron_variant		4
ATP2A2	ENST00000377685.9	c.1A>G	p.Met1?	start_lost, NMD_transcript_variant	1/20	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1361376 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 672090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 20, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1693414). Disruption of the initiator codon has been observed in individual(s) with Darier disease (PMID: 10441324, 28035777). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the ATP2A2 mRNA. The next in-frame methionine is located at codon 126. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2021	Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Identified in a family with Darier disease in published literature (Ruiz-Perez et al., 1999); This variant is associated with the following publications: (PMID: 28035777, 23356892, 10441324) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.60	D
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.93	P;P
Vest4		0.89
MutPred		0.82		Gain of catalytic residue at N3 (P = 0.1532);Gain of catalytic residue at N3 (P = 0.1532);
MVP		1.0
ClinPred		0.99	D
GERP RS		3.4
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.72
gMVP		0.62

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-110719595;