12-110281790-A-T

Variant names:

• chr12-110281790-A-T
• rs886041697
• NM_170665.4:c.1A>T

Variant summary

Our verdict is Pathogenic. The variant received 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
• Publications: 2 publications found

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]

ATP2A2 Gene-Disease associations (from GenCC):

• acrokeratosis verruciformis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Darier disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 12 pathogenic variants. Next in-frame start position is after 126 codons. Genomic position: 110296650. Lost 0.120 part of the original CDS.
• PS1: Another start lost variant in NM_170665.4 (ATP2A2) was described as [Pathogenic] in ClinVar
• 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 VariationId is 280505.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170665.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A2	NM_170665.4	MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 20	NP_733765.1	P16615-1
	ATP2A2	NM_001413013.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 19	NP_001399942.1
	ATP2A2	NM_001413014.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 22	NP_001399943.1	P16615-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A2	ENST00000539276.7	TSL:1 MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 20	ENSP00000440045.2	P16615-1
	ATP2A2	ENST00000308664.10	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 21	ENSP00000311186.6	P16615-2
	ATP2A2	ENST00000943653.1		c.1A>T	p.Met1?	initiator_codon	Exon 2 of 21	ENSP00000613712.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.15	D
PhyloP100		5.6
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.75
Sift	Benign	0.037	D
Sift4G	Benign	0.11	T
Polyphen		0.075	B
Vest4		0.78
MutPred		0.75		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
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886041697; hg19: chr12-110719595;