Genetic Variant NM_004320.6:c.1948G>T (chr16-28900764-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_004320.6(ATP2A1):c.1948G>T(p.Asp650Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D650N) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Consequence

ATP2A1
NM_004320.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.47

Publications

3 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics

ATP2A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.748

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
ATP2A1	NM_004320.6	MANE Select	c.1948G>T	p.Asp650Tyr	missense	Exon 15 of 23	NP_004311.1
ATP2A1	NM_173201.5		c.1948G>T	p.Asp650Tyr	missense	Exon 15 of 22	NP_775293.1
ATP2A1	NM_001286075.2		c.1573G>T	p.Asp525Tyr	missense	Exon 13 of 21	NP_001273004.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATP2A1	ENST00000395503.9	TSL:1 MANE Select	c.1948G>T	p.Asp650Tyr	missense	Exon 15 of 23	ENSP00000378879.5
ATP2A1	ENST00000971328.1		c.1981G>T	p.Asp661Tyr	missense	Exon 15 of 23	ENSP00000641387.1
ATP2A1	ENST00000357084.7	TSL:2	c.1948G>T	p.Asp650Tyr	missense	Exon 15 of 22	ENSP00000349595.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250284

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.75

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.1

PhyloP100

3.5

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.53

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.070

Vest4

0.44

MutPred

0.63

Loss of disorder (P = 0.036)

MVP

0.97

MPC

1.0

ClinPred

0.79

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.75

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over