chr16-28878675-G-A

Variant names:

• chr16-28878675-G-A
• rs1294417936
• NM_004320.6:c.4G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004320.6(ATP2A1):​c.4G>A​(p.Glu2Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E2E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP2A1 NM_004320.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.36
• Publications: 0 publications found

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-AS1 (HGNC:51370): (ATP2A1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 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	c.4G>A	p.Glu2Lys	missense_variant	Exon 1 of 23	ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5	c.4G>A	p.Glu2Lys	missense_variant	Exon 1 of 22		NP_775293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.4G>A	p.Glu2Lys	missense_variant	Exon 1 of 23	1	NM_004320.6	ENSP00000378879.5
ATP2A1	ENST00000357084.7	c.4G>A	p.Glu2Lys	missense_variant	Exon 1 of 22	2		ENSP00000349595.3
ATP2A1-AS1	ENST00000691192.2	n.1262C>T		non_coding_transcript_exon_variant	Exon 1 of 1
ATP2A1	ENST00000563975.1	c.-390G>A		upstream_gene_variant		2		ENSP00000458035.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brody myopathy Uncertain:1

May 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with ATP2A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2 of the ATP2A1 protein (p.Glu2Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.73	T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.8	M;M
PhyloP100		9.4
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0070	D;D
Sift4G	Benign	0.080	T;T
Polyphen		0.0080	B;B
Vest4		0.50
MutPred		0.62		Gain of ubiquitination at E2 (P = 0.0325);Gain of ubiquitination at E2 (P = 0.0325);
MVP		0.90
MPC		1.4
ClinPred		0.98	D
GERP RS		4.5
PromoterAI		-0.078	Neutral
Varity_R		0.44
gMVP		0.40

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

Other links and lift over

dbSNP: rs1294417936; hg19: chr16-28889996;