rs1042649

Variant names:

• chr12-110346569-C-T
• rs1042649
• ENST00000313432.5:n.1051C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000313432.5(ATP2A2):​n.1051C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000284 in 1,407,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: ATP2A2 ENST00000313432.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.557
• Publications: 0 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), Orphanet, PanelApp Australia, Illumina

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000313432.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A2	NM_170665.4	MANE Select	c.*99C>T		3_prime_UTR	Exon 20 of 20	NP_733765.1
	ATP2A2	NM_001413013.1		c.*99C>T		3_prime_UTR	Exon 19 of 19	NP_001399942.1
	ATP2A2	NM_001413015.1		c.*99C>T		3_prime_UTR	Exon 20 of 20	NP_001399944.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A2	ENST00000313432.5	TSL:1	n.1051C>T		non_coding_transcript_exon	Exon 2 of 2
	ATP2A2	ENST00000539276.7	TSL:1 MANE Select	c.*99C>T		3_prime_UTR	Exon 20 of 20	ENSP00000440045.2
	ATP2A2	ENST00000308664.10	TSL:1	c.2980+248C>T		intron	N/A	ENSP00000311186.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000284 AC: 4 AN: 1407386 Hom.: 0 Cov.: 30 AF XY: 0.00000430 AC XY: 3 AN XY: 697310

African (AFR) AF: 0.00 AC: 0 AN: 31748

American (AMR) AF: 0.00 AC: 0 AN: 38334

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25440

East Asian (EAS) AF: 0.00 AC: 0 AN: 36498

South Asian (SAS) AF: 0.00 AC: 0 AN: 80650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00000367 AC: 4 AN: 1089266

Other (OTH) AF: 0.00 AC: 0 AN: 58608

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.3
DANN	Benign	0.52
PhyloP100		-0.56
PromoterAI		0.0035	Neutral

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: rs1042649; hg19: chr12-110784374;