16-28894828-G-A

Position:

• chr16-28894828-G-A

Variant summary

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

The NM_004320.6(ATP2A1):​c.1294G>A​(p.Gly432Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,440 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATP2A1 NM_004320.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.23

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	Protein	UniProt
ATP2A1	NM_004320.6	c.1294G>A	p.Gly432Ser	missense_variant	12/23	ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5	c.1294G>A	p.Gly432Ser	missense_variant	12/22		NP_775293.1
ATP2A1	NM_001286075.2	c.919G>A	p.Gly307Ser	missense_variant	10/21		NP_001273004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.1294G>A	p.Gly432Ser	missense_variant	12/23	1	NM_004320.6	ENSP00000378879.5
ATP2A1	ENST00000357084.7	c.1294G>A	p.Gly432Ser	missense_variant	12/22	2		ENSP00000349595.3
ATP2A1	ENST00000536376.5	c.919G>A	p.Gly307Ser	missense_variant	10/21	2		ENSP00000443101.1
ATP2A1	ENST00000564732.1	n.321G>A		non_coding_transcript_exon_variant	4/7	5		ENSP00000457357.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249318 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

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: 0.00000137 AC: 2 AN: 1459440 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726052

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brody myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

This variant has not been reported in the literature in individuals affected with ATP2A1-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 464072). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 432 of the ATP2A1 protein (p.Gly432Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.;.
Eigen	Benign	0.053
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	1.9	L;L;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Uncertain	0.43
Sift	Uncertain	0.028	D;D;D
Sift4G	Benign	0.082	T;T;T
Polyphen		0.015	B;B;.
Vest4		0.51
MutPred		0.49		Gain of phosphorylation at G432 (P = 0.0555);Gain of phosphorylation at G432 (P = 0.0555);.;
MVP		0.94
MPC		0.84
ClinPred		0.90	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.66

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: rs752021942; hg19: chr16-28906149;