rs1860561

Variant names:

• chr12-110345436-G-A
• rs1860561
• NM_170665.4:c.2741+54G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 16 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=-0.8).
• 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 rank	MANE	Protein	UniProt
ATP2A2	NM_170665.4	c.2741+54G>A		intron_variant	Intron 18 of 19	ENST00000539276.7	NP_733765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2A2	ENST00000539276.7	c.2741+54G>A		intron_variant	Intron 18 of 19	1	NM_170665.4	ENSP00000440045.2

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

African (AFR) AF: 0.133 AC: 4444 AN: 33376

American (AMR) AF: 0.328 AC: 14632 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.0876 AC: 2286 AN: 26104

East Asian (EAS) AF: 0.00197 AC: 78 AN: 39648

South Asian (SAS) AF: 0.0972 AC: 8368 AN: 86088

European-Finnish (FIN) AF: 0.263 AC: 14006 AN: 53320

Middle Eastern (MID) AF: 0.104 AC: 598 AN: 5728

European-Non Finnish (NFE) AF: 0.225 AC: 248835 AN: 1107954

Other (OTH) AF: 0.184 AC: 11088 AN: 60248

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

African (AFR) AF: 0.141 AC: 5862 AN: 41506

American (AMR) AF: 0.287 AC: 4392 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0755 AC: 262 AN: 3470

East Asian (EAS) AF: 0.00347 AC: 18 AN: 5180

South Asian (SAS) AF: 0.0900 AC: 434 AN: 4822

European-Finnish (FIN) AF: 0.254 AC: 2689 AN: 10578

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.215 AC: 14592 AN: 67988

Other (OTH) AF: 0.186 AC: 393 AN: 2108

Alfa AF: 0.199 Hom.: 1664

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
PhyloP100		0.018
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs1860561; hg19: chr12-110783241; COSMIC: COSV57875327; COSMIC: COSV57875327;