16-28902320-C-T

Position:

• chr16-28902320-C-T

Variant summary

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

The NM_004320.6(ATP2A1):​c.2458C>T​(p.Pro820Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P820T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATP2A1 NM_004320.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.91

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]

ACMG classification

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/exons	MANE	UniProt
ATP2A1	NM_004320.6	c.2458C>T	p.Pro820Ser	missense_variant	17/23	ENST00000395503.9
ATP2A1	NM_173201.5	c.2458C>T	p.Pro820Ser	missense_variant	17/22
ATP2A1	NM_001286075.2	c.2083C>T	p.Pro695Ser	missense_variant	15/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2A1	ENST00000395503.9	c.2458C>T	p.Pro820Ser	missense_variant	17/23	1	NM_004320.6	P4
ATP2A1	ENST00000357084.7	c.2458C>T	p.Pro820Ser	missense_variant	17/22	2		A1
ATP2A1	ENST00000536376.5	c.2083C>T	p.Pro695Ser	missense_variant	15/21	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.8	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.9	D;D;D
REVEL	Uncertain	0.62
Sift	Benign	0.031	D;D;D
Sift4G	Uncertain	0.026	D;D;D
Polyphen		0.29	B;B;.
Vest4		0.51
MutPred		0.53		Loss of catalytic residue at P820 (P = 0.0018);Loss of catalytic residue at P820 (P = 0.0018);.;
MVP		0.96
MPC		0.75
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.46
gMVP		0.73

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

LitVar

Other links and lift over

dbSNP: rs149282970; hg19: chr16-28913641;