rs117350233

Variant names:

• chr16-28894527-C-G
• rs117350233
• NM_004320.6:c.1207C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-28894527-C-G
• chr16-28894527-C-T

Variant summary

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

The NM_004320.6(ATP2A1):​c.1207C>G​(p.Arg403Gly) 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 1,461,776 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. R403W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATP2A1 NM_004320.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.410
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics

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=0.27511624).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2A1	NM_004320.6	c.1207C>G	p.Arg403Gly	missense_variant	Exon 11 of 23	ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5	c.1207C>G	p.Arg403Gly	missense_variant	Exon 11 of 22		NP_775293.1
ATP2A1	NM_001286075.2	c.832C>G	p.Arg278Gly	missense_variant	Exon 9 of 21		NP_001273004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.1207C>G	p.Arg403Gly	missense_variant	Exon 11 of 23	1	NM_004320.6	ENSP00000378879.5
ATP2A1	ENST00000357084.7	c.1207C>G	p.Arg403Gly	missense_variant	Exon 11 of 22	2		ENSP00000349595.3
ATP2A1	ENST00000536376.5	c.832C>G	p.Arg278Gly	missense_variant	Exon 9 of 21	2		ENSP00000443101.1
ATP2A1	ENST00000564732.1	n.314+284C>G		intron_variant	Intron 3 of 6	5		ENSP00000457357.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461776 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727198

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

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

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: 53346

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.0061	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	-0.32	N;N;.
PhyloP100		0.41
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Benign	0.23
Sift	Benign	0.076	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.0020	B;B;.
Vest4		0.46
MutPred		0.51		Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);.;
MVP		0.79
MPC		0.62
ClinPred		0.37	T
GERP RS		3.3
Varity_R		0.22
gMVP		0.59

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: rs117350233; hg19: chr16-28905848;