dbSNP rs2071341: ATP2A1:c.2524+3G>T (chr16-28902389-G-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_004320.6(ATP2A1):c.2524+3G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0203 in 1,613,700 control chromosomes in the GnomAD database, including 2,109 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 154 hom., cov: 32)

Exomes 𝑓: 0.020 ( 1955 hom. )

Consequence

ATP2A1
NM_004320.6 splice_region, intron

Scores

Splicing: ADA: 0.9975

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.805

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 16-28902389-G-T is Benign according to our data. Variant chr16-28902389-G-T is described in ClinVar as Benign. ClinVar VariationId is 318787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.172 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	Effect	Exon Rank	Protein	UniProt
ATP2A1	NM_004320.6	MANE Select	c.2524+3G>T	splice_region intron	N/A	NP_004311.1	O14983-2
ATP2A1	NM_173201.5		c.2524+3G>T	splice_region intron	N/A	NP_775293.1	O14983-1
ATP2A1	NM_001286075.2		c.2149+3G>T	splice_region intron	N/A	NP_001273004.1	O14983-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ATP2A1	ENST00000395503.9	TSL:1 MANE Select	c.2524+3G>T	splice_region intron	N/A	ENSP00000378879.5	O14983-2
ATP2A1	ENST00000971328.1		c.2557+3G>T	splice_region intron	N/A	ENSP00000641387.1
ATP2A1	ENST00000357084.7	TSL:2	c.2524+3G>T	splice_region intron	N/A	ENSP00000349595.3	O14983-1

Frequencies

GnomAD3 genomes

AF:

0.0215

AC:

3275

AN:

152046

Hom.:

155

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0572

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.181

Gnomad SAS

AF:

0.102

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00457

Gnomad OTH

AF:

0.0187

GnomAD2 exomes

AF:

0.0492

AC:

12313

AN:

250240

AF XY:

0.0463

show subpopulations

Gnomad AFR exome

AF:

0.0153

Gnomad AMR exome

AF:

0.140

Gnomad ASJ exome

AF:

0.00130

Gnomad EAS exome

AF:

0.184

Gnomad FIN exome

AF:

0.000648

Gnomad NFE exome

AF:

0.00453

Gnomad OTH exome

AF:

0.0281

GnomAD4 exome

AF:

0.0201

AC:

29433

AN:

1461536

Hom.:

1955

Cov.:

AF XY:

0.0213

AC XY:

15490

AN XY:

727026

show subpopulations

African (AFR)

AF:

0.0138

AC:

463

AN:

33472

American (AMR)

AF:

0.127

AC:

5672

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00142

AC:

AN:

26122

East Asian (EAS)

AF:

0.218

AC:

8642

AN:

39690

South Asian (SAS)

AF:

0.0915

AC:

7891

AN:

86236

European-Finnish (FIN)

AF:

0.000674

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.0119

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00456

AC:

5073

AN:

1111810

Other (OTH)

AF:

0.0257

AC:

1551

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1677

3355

5032

6710

8387

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

472

944

1416

1888

2360

<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:

0.0215

AC:

3278

AN:

152164

Hom.:

154

Cov.:

AF XY:

0.0243

AC XY:

1810

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.0147

AC:

610

AN:

41504

American (AMR)

AF:

0.0572

AC:

875

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.181

AC:

933

AN:

5150

South Asian (SAS)

AF:

0.102

AC:

490

AN:

4822

European-Finnish (FIN)

AF:

0.000566

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00457

AC:

311

AN:

67998

Other (OTH)

AF:

0.0213

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

153

306

460

613

766

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0152

Hom.:

Bravo

AF:

0.0270

Asia WGS

AF:

0.151

AC:

524

AN:

3478

EpiCase

AF:

0.00485

EpiControl

AF:

0.00533

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Brody myopathy (2)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

0.81

Mutation Taster

=80/20

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Benign

0.66

SpliceAI score (max)

0.030

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