rs146599017

Positions:

• chr16-28903403-C-A
• chr16-28903403-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004320.6(ATP2A1):​c.2943C>A​(p.Asp981Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D981D) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATP2A1 NM_004320.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.32

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP2A1	NM_004320.6	c.2943C>A	p.Asp981Glu	missense_variant	21/23	ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5	c.2943C>A	p.Asp981Glu	missense_variant	21/22		NP_775293.1
ATP2A1	NM_001286075.2	c.2568C>A	p.Asp856Glu	missense_variant	19/21		NP_001273004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.2943C>A	p.Asp981Glu	missense_variant	21/23	1	NM_004320.6	ENSP00000378879	P4
ATP2A1	ENST00000357084.7	c.2943C>A	p.Asp981Glu	missense_variant	21/22	2		ENSP00000349595	A1
ATP2A1	ENST00000536376.5	c.2568C>A	p.Asp856Glu	missense_variant	19/21	2		ENSP00000443101
ATP2A1	ENST00000564112.1	c.33C>A	p.Asp11Glu	missense_variant	1/2	3		ENSP00000457793

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461816 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	0.13
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;.;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.23	N
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.0	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.019	D;D;D
Sift4G	Benign	0.077	T;T;T
Polyphen		0.77	P;P;.
Vest4		0.74
MutPred		0.79		Gain of ubiquitination at K985 (P = 0.102);Gain of ubiquitination at K985 (P = 0.102);.;
MVP		0.91
MPC		1.3
ClinPred		0.99	D
GERP RS		-8.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.85

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: rs146599017; hg19: chr16-28914724; COSMIC: COSV62869425; COSMIC: COSV62869425;