dbSNP rs12596913: ATP2A1:p.Thr538Thr (chr16-28898301-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004320.6(ATP2A1):c.1614G>A(p.Thr538Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0095 in 1,614,238 control chromosomes in the GnomAD database, including 476 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T538T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.016 ( 69 hom., cov: 32)

Exomes 𝑓: 0.0088 ( 407 hom. )

Consequence

ATP2A1
NM_004320.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -5.01

Publications

6 publications found

Variant links:

Genes affected

ATP2A1 (HGNC:811): (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1) This gene encodes one of the SERCA Ca(2+)-ATPases, which are intracellular pumps located in the sarcoplasmic or endoplasmic reticula of muscle cells. This enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen, and is involved in muscular excitation and contraction. Mutations in this gene cause some autosomal recessive forms of Brody disease, characterized by increasing impairment of muscular relaxation during exercise. Alternative splicing results in three transcript variants encoding different isoforms. [provided by RefSeq, Oct 2013]

ATP2A1 Gene-Disease associations (from GenCC):

Brody myopathy
Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ATP2A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 16-28898301-G-A is Benign according to our data. Variant chr16-28898301-G-A is described in ClinVar as Benign. ClinVar VariationId is 96540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.01 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004320.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP2A1	NM_004320.6	MANE Select	c.1614G>A	p.Thr538Thr	synonymous	Exon 14 of 23	NP_004311.1	O14983-2
ATP2A1	NM_173201.5		c.1614G>A	p.Thr538Thr	synonymous	Exon 14 of 22	NP_775293.1	O14983-1
ATP2A1	NM_001286075.2		c.1239G>A	p.Thr413Thr	synonymous	Exon 12 of 21	NP_001273004.1	O14983-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP2A1	ENST00000395503.9	TSL:1 MANE Select	c.1614G>A	p.Thr538Thr	synonymous	Exon 14 of 23	ENSP00000378879.5	O14983-2
ATP2A1	ENST00000971328.1		c.1647G>A	p.Thr549Thr	synonymous	Exon 14 of 23	ENSP00000641387.1
ATP2A1	ENST00000357084.7	TSL:2	c.1614G>A	p.Thr538Thr	synonymous	Exon 14 of 22	ENSP00000349595.3	O14983-1

Frequencies

GnomAD3 genomes

AF:

0.0162

AC:

2460

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0223

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00936

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.148

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.0168

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00569

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.0186

AC:

4673

AN:

251334

AF XY:

0.0169

show subpopulations

Gnomad AFR exome

AF:

0.0216

Gnomad AMR exome

AF:

0.00688

Gnomad ASJ exome

AF:

0.00764

Gnomad EAS exome

AF:

0.151

Gnomad FIN exome

AF:

0.0180

Gnomad NFE exome

AF:

0.00563

Gnomad OTH exome

AF:

0.0174

GnomAD4 exome

AF:

0.00881

AC:

12883

AN:

1461884

Hom.:

407

Cov.:

AF XY:

0.00861

AC XY:

6263

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0214

AC:

717

AN:

33480

American (AMR)

AF:

0.00675

AC:

302

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00742

AC:

194

AN:

26136

East Asian (EAS)

AF:

0.117

AC:

4628

AN:

39700

South Asian (SAS)

AF:

0.00297

AC:

256

AN:

86258

European-Finnish (FIN)

AF:

0.0182

AC:

970

AN:

53410

Middle Eastern (MID)

AF:

0.0147

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00421

AC:

4685

AN:

1112012

Other (OTH)

AF:

0.0173

AC:

1046

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

881

1762

2642

3523

4404

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

242

484

726

968

1210

<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:

0.0161

AC:

2454

AN:

152354

Hom.:

Cov.:

AF XY:

0.0168

AC XY:

1251

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0222

AC:

925

AN:

41588

American (AMR)

AF:

0.00935

AC:

143

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3472

East Asian (EAS)

AF:

0.147

AC:

766

AN:

5194

South Asian (SAS)

AF:

0.00207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0168

AC:

178

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00567

AC:

386

AN:

68034

Other (OTH)

AF:

0.0137

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

125

251

376

502

627

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.00870

Hom.:

Bravo

AF:

0.0159

Asia WGS

AF:

0.0550

AC:

192

AN:

3478

EpiCase

AF:

0.00583

EpiControl

AF:

0.00634

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Brody myopathy (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.15

(source)

DANN

Benign

0.58

PhyloP100

-5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over