12-110281466-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_170665.4(ATP2A2):c.-324G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 166,366 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (0 hom.)
• Consequence: ATP2A2 NM_170665.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.742

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BS2: High AC in GnomAd at 230 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2A2	NM_170665.4	c.-324G>A		5_prime_UTR_variant	1/20	ENST00000539276.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2A2	ENST00000539276.7	c.-324G>A		5_prime_UTR_variant	1/20	1	NM_170665.4	P3
ATP2A2	ENST00000308664.10	c.-324G>A		5_prime_UTR_variant	1/21	1		A1
ATP2A2	ENST00000552636.2	c.-258+502G>A		intron_variant		4
ATP2A2	ENST00000377685.9	c.-324G>A		5_prime_UTR_variant, NMD_transcript_variant	1/20	5

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 230 AN: 151800 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00277

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.00173 AC: 25 AN: 14458 Hom.: 0 Cov.: 0 AF XY: 0.00133 AC XY: 10 AN XY: 7494

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00431

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00137

Gnomad4 NFE exome AF: 0.00204

Gnomad4 OTH exome AF: 0.00319

GnomAD4 genome AF: 0.00151 AC: 230 AN: 151908 Hom.: 1 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74278

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00277

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00270 Hom.: 1

Bravo AF: 0.00170

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Keratosis follicularis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	13
Dann	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs543056549; hg19: chr12-110719271;