chr12-110281387-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.153

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

acrokeratosis verruciformis
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
Darier disease
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Illumina

ATP2A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 CliVar as Benign. Clinvar id is 307149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-110281387-C-G is described in CliVar 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 rank	MANE	Protein	UniProt
ATP2A2	NM_170665.4 link	c.-403C>G		5_prime_UTR_variant	Exon 1 of 20	ENST00000539276.7	NP_733765.1	P16615-1A0A0S2Z3L2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2A2	ENST00000539276.7 link	c.-403C>G		5_prime_UTR_variant	Exon 1 of 20	1	NM_170665.4	ENSP00000440045.2		P16615-1

Frequencies

GnomAD3 genomes

AF:

0.160

AC:

24251

AN:

151292

Hom.:

2638

Cov.:

show subpopulations

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:

AN:

274

Hom.:

Cov.:

AF XY:

0.142

AC XY:

AN XY:

162

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.167

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.333

AC:

AN:

European-Finnish (FIN)

AF:

0.125

AC:

AN:

Middle Eastern (MID)

AF:

0.250

AC:

AN:

European-Non Finnish (NFE)

AF:

0.154

AC:

AN:

208

Other (OTH)

AF:

0.214

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.160

AC:

24263

AN:

151398

Hom.:

2642

Cov.:

AF XY:

0.162

AC XY:

11967

AN XY:

73994

show subpopulations

African (AFR)

AF:

0.0398

AC:

1649

AN:

41468

American (AMR)

AF:

0.277

AC:

4214

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.0757

AC:

262

AN:

3460

East Asian (EAS)

AF:

0.00332

AC:

AN:

5128

South Asian (SAS)

AF:

0.0908

AC:

438

AN:

4824

European-Finnish (FIN)

AF:

0.254

AC:

2641

AN:

10402

Middle Eastern (MID)

AF:

0.134

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.214

AC:

14468

AN:

67586

Other (OTH)

AF:

0.171

AC:

360

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1004

2008

3013

4017

5021

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

258

516

774

1032

1290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Keratosis follicularis

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.59

PhyloP100

-0.15

PromoterAI

-0.040

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Mutation Taster

=298/2

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over