NM_170665.4:c.*303T>C

Variant names:

• chr12-110346773-T-C
• rs3026489
• NM_170665.4:c.*303T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 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), Illumina, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170665.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A2	NM_170665.4	MANE Select	c.*303T>C		3_prime_UTR	Exon 20 of 20	NP_733765.1	P16615-1
	ATP2A2	NM_001413013.1		c.*303T>C		3_prime_UTR	Exon 19 of 19	NP_001399942.1
	ATP2A2	NM_001413015.1		c.*303T>C		3_prime_UTR	Exon 20 of 20	NP_001399944.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A2	ENST00000539276.7	TSL:1 MANE Select	c.*303T>C		3_prime_UTR	Exon 20 of 20	ENSP00000440045.2	P16615-1
	ATP2A2	ENST00000308664.10	TSL:1	c.2980+452T>C		intron	N/A	ENSP00000311186.6	P16615-2
	ATP2A2	ENST00000553144.1	TSL:1	c.121+452T>C		intron	N/A	ENSP00000450407.2	A0A0C4DH86

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

African (AFR) AF: 0.00470 AC: 98 AN: 20866

American (AMR) AF: 0.0665 AC: 487 AN: 7328

Ashkenazi Jewish (ASJ) AF: 0.00969 AC: 108 AN: 11150

East Asian (EAS) AF: 0.000429 AC: 6 AN: 14000

South Asian (SAS) AF: 0.0498 AC: 2044 AN: 41072

European-Finnish (FIN) AF: 0.0481 AC: 482 AN: 10018

Middle Eastern (MID) AF: 0.0157 AC: 62 AN: 3944

European-Non Finnish (NFE) AF: 0.0365 AC: 32220 AN: 883584

Other (OTH) AF: 0.0333 AC: 1281 AN: 38462

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

African (AFR) AF: 0.00794 AC: 330 AN: 41576

American (AMR) AF: 0.0586 AC: 897 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5192

South Asian (SAS) AF: 0.0476 AC: 230 AN: 4828

European-Finnish (FIN) AF: 0.0499 AC: 529 AN: 10610

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0381 AC: 2595 AN: 68028

Other (OTH) AF: 0.0327 AC: 69 AN: 2112

Alfa AF: 0.0297 Hom.: 41

Bravo AF: 0.0305

Asia WGS AF: 0.0210 AC: 73 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.6
DANN	Benign	0.82
PhyloP100		0.057
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=99/1	polymorphism

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: rs3026489; hg19: chr12-110784578;