rs56243033

chr12-110342302-G-Achr12-110342302-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_170665.4(ATP2A2):c.2172G>A(p.Ala724=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0634 in 1,614,176 control chromosomes in the GnomAD database, including 3,631 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (228 hom., cov: 32)
  • Exomes 𝑓: 0.065 (3403 hom.)
• Consequence: ATP2A2 NM_170665.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.888

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 12-110342302-G-A is Benign according to our data. Variant chr12-110342302-G-A is described in ClinVar as [Benign]. Clinvar id is 307178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.888 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.071 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2A2	NM_170665.4	c.2172G>A	p.Ala724=	synonymous_variant	15/20	ENST00000539276.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2A2	ENST00000539276.7	c.2172G>A	p.Ala724=	synonymous_variant	15/20	1	NM_170665.4	P3
ATP2A2	ENST00000308664.10	c.2172G>A	p.Ala724=	synonymous_variant	15/21	1		A1
ATP2A2	ENST00000548169.2	c.1845G>A	p.Ala615=	synonymous_variant	11/16	2
ATP2A2	ENST00000377685.9	c.*2012G>A		3_prime_UTR_variant, NMD_transcript_variant	14/20	5

Frequencies

GnomAD3 genomes AF: 0.0467 AC: 7113 AN: 152170 Hom.: 228 Cov.: 32

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.0615

Gnomad AMR AF: 0.0275

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0482

Gnomad FIN AF: 0.0752

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.0726

Gnomad OTH AF: 0.0330

GnomAD3 exomes AF: 0.0527 AC: 13260 AN: 251464 Hom.: 487 AF XY: 0.0551 AC XY: 7492 AN XY: 135910

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.0230

Gnomad ASJ exome AF: 0.0287

Gnomad EAS exome AF: 0.000761

Gnomad SAS exome AF: 0.0533

Gnomad FIN exome AF: 0.0715

Gnomad NFE exome AF: 0.0746

Gnomad OTH exome AF: 0.0536

GnomAD4 exome AF: 0.0652 AC: 95276 AN: 1461888 Hom.: 3403 Cov.: 32 AF XY: 0.0656 AC XY: 47721 AN XY: 727248

Gnomad4 AFR exome AF: 0.00944

Gnomad4 AMR exome AF: 0.0236

Gnomad4 ASJ exome AF: 0.0312

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0546

Gnomad4 FIN exome AF: 0.0747

Gnomad4 NFE exome AF: 0.0726

Gnomad4 OTH exome AF: 0.0552

GnomAD4 genome AF: 0.0467 AC: 7115 AN: 152288 Hom.: 228 Cov.: 32 AF XY: 0.0446 AC XY: 3323 AN XY: 74474

Gnomad4 AFR AF: 0.0114

Gnomad4 AMR AF: 0.0275

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0484

Gnomad4 FIN AF: 0.0752

Gnomad4 NFE AF: 0.0727

Gnomad4 OTH AF: 0.0327

Alfa AF: 0.0542 Hom.: 160

Bravo AF: 0.0405

Asia WGS AF: 0.0180 AC: 63 AN: 3478

EpiCase AF: 0.0663

EpiControl AF: 0.0658

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 17439322, 20687374) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

Keratosis follicularis Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Acrokeratosis verruciformis of Hopf Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.56
Dann	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs56243033; hg19: chr12-110780107;