12-110346773-T-C

Position:

• chr12-110346773-T-C

Variant summary

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

The NM_170665.4(ATP2A2):​c.*303T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0351 in 1,182,740 control chromosomes in the GnomAD database, including 886 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 0.031 (112 hom., cov: 32)
  • Exomes 𝑓: 0.036 (774 hom.)
• Consequence: ATP2A2 NM_170665.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0570

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=-0.77).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2A2	NM_170665.4	c.*303T>C		3_prime_UTR_variant	20/20	ENST00000539276.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2A2	ENST00000539276.7	c.*303T>C		3_prime_UTR_variant	20/20	1	NM_170665.4	P3

Frequencies

GnomAD3 genomes AF: 0.0311 AC: 4731 AN: 152198 Hom.: 113 Cov.: 32

Gnomad AFR AF: 0.00796

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0585

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0478

Gnomad FIN AF: 0.0499

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0381

Gnomad OTH AF: 0.0330

GnomAD4 exome AF: 0.0357 AC: 36788 AN: 1030424 Hom.: 774 Cov.: 29 AF XY: 0.0361 AC XY: 17665 AN XY: 489474

Gnomad4 AFR exome AF: 0.00470

Gnomad4 AMR exome AF: 0.0665

Gnomad4 ASJ exome AF: 0.00969

Gnomad4 EAS exome AF: 0.000429

Gnomad4 SAS exome AF: 0.0498

Gnomad4 FIN exome AF: 0.0481

Gnomad4 NFE exome AF: 0.0365

Gnomad4 OTH exome AF: 0.0333

GnomAD4 genome AF: 0.0311 AC: 4734 AN: 152316 Hom.: 112 Cov.: 32 AF XY: 0.0322 AC XY: 2399 AN XY: 74482

Gnomad4 AFR AF: 0.00794

Gnomad4 AMR AF: 0.0586

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0476

Gnomad4 FIN AF: 0.0499

Gnomad4 NFE AF: 0.0381

Gnomad4 OTH AF: 0.0327

Alfa AF: 0.0254 Hom.: 26

Bravo AF: 0.0305

Asia WGS AF: 0.0210 AC: 73 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.6
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs3026489; hg19: chr12-110784578;