NM_004320.6:c.2758C>G

Variant names:

• chr16-28903043-C-G
• rs897301304
• NM_004320.6:c.2758C>G

Variant summary

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

The NM_004320.6(ATP2A1):​c.2758C>G​(p.Gln920Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,648 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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: 7.89
• 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 Gene-Disease associations (from GenCC):

• Brody myopathy

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004320.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A1	NM_004320.6	MANE Select	c.2758C>G	p.Gln920Glu	missense	Exon 20 of 23	NP_004311.1	O14983-2
	ATP2A1	NM_173201.5		c.2758C>G	p.Gln920Glu	missense	Exon 20 of 22	NP_775293.1	O14983-1
	ATP2A1	NM_001286075.2		c.2383C>G	p.Gln795Glu	missense	Exon 18 of 21	NP_001273004.1	O14983-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A1	ENST00000395503.9	TSL:1 MANE Select	c.2758C>G	p.Gln920Glu	missense	Exon 20 of 23	ENSP00000378879.5	O14983-2
	ATP2A1	ENST00000971328.1		c.2791C>G	p.Gln931Glu	missense	Exon 20 of 23	ENSP00000641387.1
	ATP2A1	ENST00000357084.7	TSL:2	c.2758C>G	p.Gln920Glu	missense	Exon 20 of 22	ENSP00000349595.3	O14983-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461648 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727156

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	0.075
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	1.7	L
PhyloP100		7.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.68
Sift	Benign	0.43	T
Sift4G	Benign	0.62	T
Polyphen		0.0030	B
Vest4		0.76
MutPred		0.53		Loss of sheet (P = 0.0315)
MVP		0.95
MPC		1.3
ClinPred		0.98	D
GERP RS		4.7
PromoterAI		-0.0055	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.75
Mutation Taster		=50/50

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: rs897301304; hg19: chr16-28914364;