17-3930413-C-G

Variant names:

• chr17-3930413-C-G
• rs368619808
• NM_005173.4:c.2632G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005173.4(ATP2A3):​c.2632G>C​(p.Glu878Gln) 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 1,461,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E878K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATP2A3 NM_005173.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.560
• Publications: 0 publications found

Genes affected

ATP2A3 (HGNC:813): (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 3) 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 calcium sequestration associated with muscular excitation and contraction. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26697278).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005173.4. 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
	ATP2A3	NM_005173.4	MANE Select	c.2632G>C	p.Glu878Gln	missense	Exon 18 of 21	NP_005164.2
	ATP2A3	NM_174953.3		c.2632G>C	p.Glu878Gln	missense	Exon 18 of 23	NP_777613.1	Q93084-5
	ATP2A3	NM_174954.3		c.2632G>C	p.Glu878Gln	missense	Exon 18 of 23	NP_777614.1	Q93084-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A3	ENST00000397041.8	TSL:1 MANE Select	c.2632G>C	p.Glu878Gln	missense	Exon 18 of 21	ENSP00000380234.3	Q93084-2
	ATP2A3	ENST00000397043.7	TSL:1	c.2632G>C	p.Glu878Gln	missense	Exon 18 of 21	ENSP00000380236.3	Q93084-4
	ATP2A3	ENST00000359983.7	TSL:5	c.2632G>C	p.Glu878Gln	missense	Exon 18 of 23	ENSP00000353072.3	Q93084-5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461618 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727098

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

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111956

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	12
DANN	Benign	0.91
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.56
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.83	N
REVEL	Uncertain	0.38
Sift	Benign	0.31	T
Sift4G	Benign	0.46	T
Polyphen		0.0020	B
Vest4		0.39
MutPred		0.48		Loss of sheet (P = 0.1158)
MVP		0.55
MPC		0.59
ClinPred		0.35	T
GERP RS		1.7
PromoterAI		-0.067	Neutral
Varity_R		0.095
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs368619808; hg19: chr17-3833707;