12-110281387-C-G

Position:

• chr12-110281387-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_170665.4(ATP2A2):​c.-403C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 151,672 control chromosomes in the GnomAD database, including 2,646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2642 hom., cov: 32)
  • Exomes 𝑓: 0.15 (4 hom.)
• Consequence: ATP2A2 NM_170665.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.153

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 12-110281387-C-G is Benign according to our data. Variant chr12-110281387-C-G is described in ClinVar as [Benign]. Clinvar id is 307149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2A2	NM_170665.4	c.-403C>G		5_prime_UTR_variant	1/20	ENST00000539276.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2A2	ENST00000539276.7	c.-403C>G		5_prime_UTR_variant	1/20	1	NM_170665.4	P3
ATP2A2	ENST00000308664.10	c.-403C>G		5_prime_UTR_variant	1/21	1		A1
ATP2A2	ENST00000552636.2	c.-258+423C>G		intron_variant		4
ATP2A2	ENST00000377685.9	c.-403C>G		5_prime_UTR_variant, NMD_transcript_variant	1/20	5

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24251 AN: 151292 Hom.: 2638 Cov.: 32

Gnomad AFR AF: 0.0399

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.0757

Gnomad EAS AF: 0.00311

Gnomad SAS AF: 0.0903

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.174

GnomAD4 exome AF: 0.146 AC: 40 AN: 274 Hom.: 4 Cov.: 0 AF XY: 0.142 AC XY: 23 AN XY: 162

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.167

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.333

Gnomad4 FIN exome AF: 0.125

Gnomad4 NFE exome AF: 0.154

Gnomad4 OTH exome AF: 0.214

GnomAD4 genome AF: 0.160 AC: 24263 AN: 151398 Hom.: 2642 Cov.: 32 AF XY: 0.162 AC XY: 11967 AN XY: 73994

Gnomad4 AFR AF: 0.0398

Gnomad4 AMR AF: 0.277

Gnomad4 ASJ AF: 0.0757

Gnomad4 EAS AF: 0.00332

Gnomad4 SAS AF: 0.0908

Gnomad4 FIN AF: 0.254

Gnomad4 NFE AF: 0.214

Gnomad4 OTH AF: 0.171

Alfa AF: 0.108 Hom.: 189

Bravo AF: 0.156

Asia WGS AF: 0.0650 AC: 222 AN: 3404

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.78
CADD	Benign	6.5
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3026433; hg19: chr12-110719192;