rs61626938

Variant names:

• chr16-28900790-C-A
• rs61626938
• NM_004320.6:c.1974C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-28900790-C-A
• chr16-28900790-C-G
• chr16-28900790-C-T

Variant summary

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

The NM_004320.6(ATP2A1):​c.1974C>A​(p.Phe658Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATP2A1 NM_004320.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.81

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 rank	MANE	Protein	UniProt
ATP2A1	NM_004320.6	c.1974C>A	p.Phe658Leu	missense_variant	Exon 15 of 23	ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5	c.1974C>A	p.Phe658Leu	missense_variant	Exon 15 of 22		NP_775293.1
ATP2A1	NM_001286075.2	c.1599C>A	p.Phe533Leu	missense_variant	Exon 13 of 21		NP_001273004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.1974C>A	p.Phe658Leu	missense_variant	Exon 15 of 23	1	NM_004320.6	ENSP00000378879.5
ATP2A1	ENST00000357084.7	c.1974C>A	p.Phe658Leu	missense_variant	Exon 15 of 22	2		ENSP00000349595.3
ATP2A1	ENST00000536376.5	c.1599C>A	p.Phe533Leu	missense_variant	Exon 13 of 21	2		ENSP00000443101.1
ATP2A1	ENST00000564732.1	n.*617C>A		downstream_gene_variant		5		ENSP00000457357.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brody myopathy Uncertain:1

Feb 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 658 of the ATP2A1 protein (p.Phe658Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ATP2A1-related conditions. 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"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	0.086
DANN	Benign	0.95
DEOGEN2	Uncertain	0.71	D;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.15	N
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	0.34	N;N;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Uncertain	0.54
Sift	Benign	0.032	D;D;D
Sift4G	Benign	0.31	T;T;T
Polyphen		0.0070	B;B;.
Vest4		0.76
MutPred		0.65		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);.;
MVP		0.76
MPC		1.4
ClinPred		0.99	D
GERP RS		-11
Varity_R		0.54
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: rs61626938; hg19: chr16-28912111; COSMIC: COSV100707002; COSMIC: COSV100707002;