rs3026452

Variant names:

• chr12-110290044-A-G
• rs3026452
• NM_170665.4:c.220-1976A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_170665.4(ATP2A2):​c.220-1976A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0302 in 152,310 control chromosomes in the GnomAD database, including 80 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 0.030 (80 hom., cov: 32)
• Consequence: ATP2A2 NM_170665.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0150
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2A2	NM_170665.4	c.220-1976A>G		intron_variant	Intron 3 of 19	ENST00000539276.7	NP_733765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2A2	ENST00000539276.7	c.220-1976A>G		intron_variant	Intron 3 of 19	1	NM_170665.4	ENSP00000440045.2
ATP2A2	ENST00000308664.10	c.220-1976A>G		intron_variant	Intron 3 of 20	1		ENSP00000311186.6
ATP2A2	ENST00000552636.2	c.-156-1976A>G		intron_variant	Intron 3 of 4	4		ENSP00000447406.2
ATP2A2	ENST00000377685.9	n.*60-1976A>G		intron_variant	Intron 2 of 19	5		ENSP00000366913.4

Frequencies

GnomAD3 genomes AF: 0.0302 AC: 4593 AN: 152192 Hom.: 79 Cov.: 32

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0209

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.0757

Gnomad SAS AF: 0.0501

Gnomad FIN AF: 0.0363

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0325

Gnomad OTH AF: 0.0311

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

GnomAD4 genome AF: 0.0302 AC: 4607 AN: 152310 Hom.: 80 Cov.: 32 AF XY: 0.0308 AC XY: 2292 AN XY: 74470

African (AFR) AF: 0.0221 AC: 918 AN: 41576

American (AMR) AF: 0.0209 AC: 319 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3472

East Asian (EAS) AF: 0.0760 AC: 394 AN: 5182

South Asian (SAS) AF: 0.0509 AC: 246 AN: 4830

European-Finnish (FIN) AF: 0.0363 AC: 385 AN: 10612

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0325 AC: 2209 AN: 68022

Other (OTH) AF: 0.0345 AC: 73 AN: 2114

Alfa AF: 0.0311 Hom.: 23

Bravo AF: 0.0293

Asia WGS AF: 0.0660 AC: 230 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.27
DANN	Benign	0.53
PhyloP100		0.015
Mutation Taster		=99/1	polymorphism (auto)

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: rs3026452; hg19: chr12-110727849;