rs4630352

Positions:

• chr12-110309614-G-A
• chr12-110309614-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_170665.4(ATP2A2):​c.463+12877G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 151,854 control chromosomes in the GnomAD database, including 14,446 homozygotes. 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: 𝑓 0.41 (14446 hom., cov: 30)
• Consequence: ATP2A2 NM_170665.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.482

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP2A2	NM_170665.4	c.463+12877G>A		intron_variant		ENST00000539276.7	NP_733765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2A2	ENST00000539276.7	c.463+12877G>A		intron_variant		1	NM_170665.4	ENSP00000440045	P3

Frequencies

GnomAD3 genomes AF: 0.413 AC: 62671 AN: 151736 Hom.: 14402 Cov.: 30

Gnomad AFR AF: 0.606

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.424

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.0176

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.349

Gnomad OTH AF: 0.393

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.413 AC: 62775 AN: 151854 Hom.: 14446 Cov.: 30 AF XY: 0.409 AC XY: 30349 AN XY: 74190

Gnomad4 AFR AF: 0.607

Gnomad4 AMR AF: 0.424

Gnomad4 ASJ AF: 0.277

Gnomad4 EAS AF: 0.0178

Gnomad4 SAS AF: 0.211

Gnomad4 FIN AF: 0.393

Gnomad4 NFE AF: 0.349

Gnomad4 OTH AF: 0.388

Alfa AF: 0.406 Hom.: 1949

Bravo AF: 0.424

Asia WGS AF: 0.176 AC: 614 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.61
DANN	Benign	0.25

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: rs4630352; hg19: chr12-110747419;