rs115016152

Variant names:

• chr12-110332668-T-C
• rs115016152
• NM_170665.4:c.1167T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The ENST00000539276.7(ATP2A2):​c.1167T>C​(p.Tyr389Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000272 in 1,612,200 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: ATP2A2 ENST00000539276.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.786
• 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.

• BP6: Variant 12-110332668-T-C is Benign according to our data. Variant chr12-110332668-T-C is described in ClinVar as Benign. ClinVar VariationId is 307170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 205 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000539276.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A2	NM_170665.4	MANE Select	c.1167T>C	p.Tyr389Tyr	synonymous	Exon 9 of 20	NP_733765.1
	ATP2A2	NM_001413013.1		c.1062T>C	p.Tyr354Tyr	synonymous	Exon 8 of 19	NP_001399942.1
	ATP2A2	NM_001413014.1		c.1167T>C	p.Tyr389Tyr	synonymous	Exon 9 of 22	NP_001399943.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A2	ENST00000539276.7	TSL:1 MANE Select	c.1167T>C	p.Tyr389Tyr	synonymous	Exon 9 of 20	ENSP00000440045.2
	ATP2A2	ENST00000308664.10	TSL:1	c.1167T>C	p.Tyr389Tyr	synonymous	Exon 9 of 21	ENSP00000311186.6
	ATP2A2	ENST00000548169.2	TSL:2	c.837T>C	p.Tyr279Tyr	synonymous	Exon 5 of 16	ENSP00000449454.2

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 203 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00480

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000374 AC: 94 AN: 251460 AF XY: 0.000302

Gnomad AFR exome AF: 0.00492

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000160 AC: 233 AN: 1459848 Hom.: 1 Cov.: 30 AF XY: 0.000147 AC XY: 107 AN XY: 726376

African (AFR) AF: 0.00586 AC: 196 AN: 33444

American (AMR) AF: 0.000380 AC: 17 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1110172

Other (OTH) AF: 0.000199 AC: 12 AN: 60330

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.00134 AC XY: 100 AN XY: 74504

African (AFR) AF: 0.00483 AC: 201 AN: 41586

American (AMR) AF: 0.000196 AC: 3 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000862 Hom.: 0

Bravo AF: 0.00158

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Keratosis follicularis (2)
-	-	2	not provided (2)
-	-	1	Acrokeratosis verruciformis of Hopf (1)
-	-	1	ATP2A2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.038
DANN	Benign	0.46
PhyloP100		-0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs115016152; hg19: chr12-110770473;