Genetic Variant ATP2A1:p.Thr22Met (chr16-28878736-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004320.6(ATP2A1):c.65C>T(p.Thr22Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000024 in 1,461,050 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

ATP2A1
NM_004320.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.42

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2A1	NM_004320.6 link	c.65C>T	p.Thr22Met	missense_variant	Exon 1 of 23	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.65C>T	p.Thr22Met	missense_variant	Exon 1 of 23	1	NM_004320.6	ENSP00000378879.5		O14983-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249862

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135114

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000873

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1461050

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726766

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Feb 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.65C>T (p.T22M) alteration is located in exon 1 (coding exon 1) of the ATP2A1 gene. This alteration results from a C to T substitution at nucleotide position 65, causing the threonine (T) at amino acid position 22 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

T;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Benign

0.55

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.44

T;T

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.7

M;M

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.4

N;N

REVEL

Uncertain

0.36

Sift

Benign

0.068

T;T

Sift4G

Benign

0.062

T;T

Polyphen

0.73

P;P

Vest4

0.33

MutPred

0.34

Loss of disorder (P = 0.1002);Loss of disorder (P = 0.1002);

MVP

0.92

MPC

0.83

ClinPred

0.75

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.073

gMVP

0.51

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over