rs1860561

chr12-110345436-G-A

Variant summary

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

The NM_170665.4(ATP2A2):c.2741+54G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,609,260 control chromosomes in the GnomAD database, including 37,709 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 0.19 (3091 hom., cov: 32)
  • Exomes 𝑓: 0.21 (34618 hom.)
• Consequence: ATP2A2 NM_170665.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0180

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=-0.8).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2A2	NM_170665.4	c.2741+54G>A		intron_variant		ENST00000539276.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2A2	ENST00000539276.7	c.2741+54G>A		intron_variant		1	NM_170665.4	P3

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28827 AN: 152028 Hom.: 3084 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.0755

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.0895

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.189

GnomAD4 exome AF: 0.209 AC: 304335 AN: 1457114 Hom.: 34618 Cov.: 32 AF XY: 0.204 AC XY: 147849 AN XY: 725194

Gnomad4 AFR exome AF: 0.133

Gnomad4 AMR exome AF: 0.328

Gnomad4 ASJ exome AF: 0.0876

Gnomad4 EAS exome AF: 0.00197

Gnomad4 SAS exome AF: 0.0972

Gnomad4 FIN exome AF: 0.263

Gnomad4 NFE exome AF: 0.225

Gnomad4 OTH exome AF: 0.184

GnomAD4 genome AF: 0.190 AC: 28862 AN: 152146 Hom.: 3091 Cov.: 32 AF XY: 0.190 AC XY: 14105 AN XY: 74368

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.287

Gnomad4 ASJ AF: 0.0755

Gnomad4 EAS AF: 0.00347

Gnomad4 SAS AF: 0.0900

Gnomad4 FIN AF: 0.254

Gnomad4 NFE AF: 0.215

Gnomad4 OTH AF: 0.186

Alfa AF: 0.200 Hom.: 1508

Bravo AF: 0.189

Asia WGS AF: 0.0770 AC: 268 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	2.1
Dann	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1860561; hg19: chr12-110783241; COSMIC: COSV57875327; COSMIC: COSV57875327;