rs201929640

Positions:

• chr12-110281780-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_170665.4(ATP2A2):​c.-10C>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 0.00899 in 1,492,406 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0092 (69 hom.)
• Consequence: ATP2A2 NM_170665.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.352

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 12-110281780-C-G is Benign according to our data. Variant chr12-110281780-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 307158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-110281780-C-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 1045 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2A2	NM_170665.4	c.-10C>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.-10C>G		5_prime_UTR_variant	1/20	1	NM_170665.4	P3
ATP2A2	ENST00000308664.10	c.-10C>G		5_prime_UTR_variant	1/21	1		A1
ATP2A2	ENST00000552636.2	c.-258+816C>G		intron_variant		4
ATP2A2	ENST00000377685.9	c.-10C>G		5_prime_UTR_variant, NMD_transcript_variant	1/20	5

Frequencies

GnomAD3 genomes AF: 0.00688 AC: 1046 AN: 152046 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00786

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0171

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00943

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00752 AC: 884 AN: 117624 Hom.: 8 AF XY: 0.00719 AC XY: 456 AN XY: 63442

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00480

Gnomad ASJ exome AF: 0.00172

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00432

Gnomad FIN exome AF: 0.0185

Gnomad NFE exome AF: 0.00893

Gnomad OTH exome AF: 0.00799

GnomAD4 exome AF: 0.00923 AC: 12376 AN: 1340252 Hom.: 69 Cov.: 30 AF XY: 0.00910 AC XY: 6012 AN XY: 660728

Gnomad4 AFR exome AF: 0.000981

Gnomad4 AMR exome AF: 0.00495

Gnomad4 ASJ exome AF: 0.00135

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00526

Gnomad4 FIN exome AF: 0.0178

Gnomad4 NFE exome AF: 0.0101

Gnomad4 OTH exome AF: 0.00624

GnomAD4 genome AF: 0.00687 AC: 1045 AN: 152154 Hom.: 1 Cov.: 32 AF XY: 0.00678 AC XY: 504 AN XY: 74372

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00778

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0171

Gnomad4 NFE AF: 0.00943

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00627 Hom.: 2

Bravo AF: 0.00598

Asia WGS AF: 0.00144 AC: 5 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Keratosis follicularis Benign:3

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	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Associated with reduced mRNA expression and risk for colon cancer. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ATP2A2: BS1, BS2 -

Acrokeratosis verruciformis of Hopf Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Keratosis follicularis;C0265971:Acrokeratosis verruciformis of Hopf Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 21, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.81
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: rs201929640; hg19: chr12-110719585;