rs3026490

Variant names:

• chr12-110347704-G-A
• rs3026490
• ENST00000313432.5:n.2186G>A

Variant summary

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

The ENST00000313432.5(ATP2A2):​n.2186G>A 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 0.00475 in 1,166,504 control chromosomes in the GnomAD database, including 239 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 0.024 (148 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (91 hom.)
• Consequence: ATP2A2 ENST00000313432.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.519
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2A2	NM_170665.4	c.*1234G>A		3_prime_UTR_variant	Exon 20 of 20	ENST00000539276.7	NP_733765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2A2	ENST00000539276.7	c.*1234G>A		3_prime_UTR_variant	Exon 20 of 20	1	NM_170665.4	ENSP00000440045.2

Frequencies

GnomAD3 genomes AF: 0.0235 AC: 3570 AN: 152178 Hom.: 147 Cov.: 32

Gnomad AFR AF: 0.0808

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0172

GnomAD4 exome AF: 0.00194 AC: 1966 AN: 1014208 Hom.: 91 Cov.: 34 AF XY: 0.00179 AC XY: 868 AN XY: 484114

African (AFR) AF: 0.0793 AC: 1646 AN: 20750

American (AMR) AF: 0.00476 AC: 53 AN: 11126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9292

East Asian (EAS) AF: 0.00 AC: 0 AN: 11486

South Asian (SAS) AF: 0.000170 AC: 9 AN: 52950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7854

Middle Eastern (MID) AF: 0.00224 AC: 5 AN: 2230

European-Non Finnish (NFE) AF: 0.000123 AC: 106 AN: 862462

Other (OTH) AF: 0.00408 AC: 147 AN: 36058

GnomAD4 genome AF: 0.0235 AC: 3579 AN: 152296 Hom.: 148 Cov.: 32 AF XY: 0.0226 AC XY: 1684 AN XY: 74484

African (AFR) AF: 0.0808 AC: 3357 AN: 41558

American (AMR) AF: 0.0107 AC: 163 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68020

Other (OTH) AF: 0.0170 AC: 36 AN: 2116

Alfa AF: 0.0140 Hom.: 14

Bravo AF: 0.0269

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.2
DANN	Benign	0.74
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3026490; hg19: chr12-110785509;