Genetic Variant ATP2A1:c.219+561C>T (chr16-28880144-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004320.6(ATP2A1):c.219+561C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 994,692 control chromosomes in the GnomAD database, including 74,422 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.34 ( 9510 hom., cov: 32)

Exomes 𝑓: 0.39 ( 64912 hom. )

Consequence

ATP2A1
NM_004320.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.501

Publications

28 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 links:

ATP2A1-AS1 (HGNC:51370): (ATP2A1 antisense RNA 1)

ATP2A1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2A1	NM_004320.6 link	c.219+561C>T		intron_variant	Intron 3 of 22	ENST00000395503.9	NP_004311.1	O14983-2Q7Z675

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9 link	c.219+561C>T		intron_variant	Intron 3 of 22	1	NM_004320.6	ENSP00000378879.5		O14983-2

Frequencies

GnomAD3 genomes

AF:

0.341

AC:

51765

AN:

151978

Hom.:

9481

Cov.:

show subpopulations

Gnomad AFR

AF:

0.264

Gnomad AMI

AF:

0.244

Gnomad AMR

AF:

0.404

Gnomad ASJ

AF:

0.268

Gnomad EAS

AF:

0.121

Gnomad SAS

AF:

0.216

Gnomad FIN

AF:

0.422

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.392

Gnomad OTH

AF:

0.306

GnomAD4 exome

AF:

0.390

AC:

328250

AN:

842596

Hom.:

64912

Cov.:

AF XY:

0.390

AC XY:

152015

AN XY:

389554

show subpopulations

African (AFR)

AF:

0.246

AC:

3890

AN:

15830

American (AMR)

AF:

0.449

AC:

731

AN:

1628

Ashkenazi Jewish (ASJ)

AF:

0.257

AC:

1350

AN:

5254

East Asian (EAS)

AF:

0.104

AC:

387

AN:

3726

South Asian (SAS)

AF:

0.220

AC:

3730

AN:

16980

European-Finnish (FIN)

AF:

0.405

AC:

196

AN:

484

Middle Eastern (MID)

AF:

0.235

AC:

391

AN:

1662

European-Non Finnish (NFE)

AF:

0.400

AC:

307942

AN:

769202

Other (OTH)

AF:

0.346

AC:

9633

AN:

27830

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

9838

19676

29514

39352

49190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12786

25572

38358

51144

63930

<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:

0.341

AC:

51858

AN:

152096

Hom.:

9510

Cov.:

AF XY:

0.339

AC XY:

25230

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.265

AC:

11007

AN:

41536

American (AMR)

AF:

0.405

AC:

6195

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.268

AC:

930

AN:

3470

East Asian (EAS)

AF:

0.120

AC:

622

AN:

5164

South Asian (SAS)

AF:

0.216

AC:

1042

AN:

4828

European-Finnish (FIN)

AF:

0.422

AC:

4459

AN:

10566

Middle Eastern (MID)

AF:

0.224

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.392

AC:

26660

AN:

67930

Other (OTH)

AF:

0.310

AC:

655

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1614

3228

4843

6457

8071

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

504

1008

1512

2016

2520

<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:

0.374

Hom.:

2019

Bravo

AF:

0.339

Asia WGS

AF:

0.274

AC:

950

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

5.6

(source)

DANN

Benign

0.68

PhyloP100

0.50

PromoterAI

0.019

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over