12-110281775-C-T

Position:

• chr12-110281775-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_170665.4(ATP2A2):​c.-15C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,485,860 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: ATP2A2 NM_170665.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.07

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 12-110281775-C-T is Benign according to our data. Variant chr12-110281775-C-T is described in ClinVar as [Benign]. Clinvar id is 307157.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2A2	NM_170665.4	c.-15C>T		5_prime_UTR_variant	1/20	ENST00000539276.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2A2	ENST00000539276.7	c.-15C>T		5_prime_UTR_variant	1/20	1	NM_170665.4	P3
ATP2A2	ENST00000308664.10	c.-15C>T		5_prime_UTR_variant	1/21	1		A1
ATP2A2	ENST00000552636.2	c.-258+811C>T		intron_variant		4
ATP2A2	ENST00000377685.9	c.-15C>T		5_prime_UTR_variant, NMD_transcript_variant	1/20	5

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000337 AC: 38 AN: 112596 Hom.: 2 AF XY: 0.000263 AC XY: 16 AN XY: 60910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000179

Gnomad ASJ exome AF: 0.00206

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000451

Gnomad OTH exome AF: 0.000344

GnomAD4 exome AF: 0.000220 AC: 294 AN: 1333648 Hom.: 1 Cov.: 29 AF XY: 0.000215 AC XY: 141 AN XY: 657260

Gnomad4 AFR exome AF: 0.0000367

Gnomad4 AMR exome AF: 0.0000720

Gnomad4 ASJ exome AF: 0.00280

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000208

Gnomad4 OTH exome AF: 0.000183

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74414

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000507 Hom.: 1

Bravo AF: 0.000363

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Keratosis follicularis Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Benign	0.93
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0

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: rs373966549; hg19: chr12-110719580;