rs55984131

Positions:

chr12-110296601-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_170665.4(ATP2A2):c.327A>G(p.Glu109=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.009 in 1,614,132 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0068 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0092 ( 73 hom. )

Consequence

ATP2A2
NM_170665.4 splice_region, synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.31

Variant links:

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]

ATP2A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008938611).

BP6

Variant 12-110296601-A-G is Benign according to our data. Variant chr12-110296601-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 307165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-110296601-A-G is described in Lovd as [Benign]. Variant chr12-110296601-A-G is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=2.31 with no splicing effect.

BS2

High AC in GnomAd4 at 1043 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2A2	NM_170665.4 linkuse as main transcript	c.327A>G	p.Glu109=	splice_region_variant, synonymous_variant	5/20	ENST00000539276.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2A2	ENST00000539276.7 linkuse as main transcript	c.327A>G	p.Glu109=	splice_region_variant, synonymous_variant	5/20	1	NM_170665.4	P3	P16615-1

Frequencies

GnomAD3 genomes

AF:

0.00686

AC:

1044

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00166

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00779

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.0170

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00941

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00749

AC:

1883

AN:

251390

Hom.:

AF XY:

0.00763

AC XY:

1037

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00141

Gnomad AMR exome

AF:

0.00483

Gnomad ASJ exome

AF:

0.00198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00457

Gnomad FIN exome

AF:

0.0190

Gnomad NFE exome

AF:

0.00934

Gnomad OTH exome

AF:

0.00978

GnomAD4 exome

AF:

0.00922

AC:

13479

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00913

AC XY:

6641

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.00116

Gnomad4 AMR exome

AF:

0.00512

Gnomad4 ASJ exome

AF:

0.00145

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00559

Gnomad4 FIN exome

AF:

0.0182

Gnomad4 NFE exome

AF:

0.0102

Gnomad4 OTH exome

AF:

0.00647

GnomAD4 genome

AF:

0.00685

AC:

1043

AN:

152326

Hom.:

Cov.:

AF XY:

0.00675

AC XY:

503

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00166

Gnomad4 AMR

AF:

0.00772

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.0170

Gnomad4 NFE

AF:

0.00941

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00839

Hom.:

Bravo

AF:

0.00600

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00895

AC:

ExAC

AF:

0.00730

AC:

886

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00807

EpiControl

AF:

0.00889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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: ExAC frequency, risk for lung cancer, silent variant -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ATP2A2: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

Keratosis follicularis

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
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	- -

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_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.87

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.82

MetaRNN

Benign

0.0089

MetaSVM

Benign

-0.70

MutationTaster

Benign

0.58

D;D;D;D

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.42

Vest4

0.18

MVP

0.84

ClinPred

0.042

GERP RS

0.34

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over