16-28902318-GC-GCCC
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2
The NM_004320.6(ATP2A1):c.2463_2464dupCC(p.Arg822ProfsTer50) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,154 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
ATP2A1
NM_004320.6 frameshift
NM_004320.6 frameshift
Scores
Not classified
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 0.140
Publications
9 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 myopathyInheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 10 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
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.2463_2464dupCC | p.Arg822ProfsTer50 | frameshift_variant | Exon 17 of 23 | ENST00000395503.9 | NP_004311.1 | |
| ATP2A1 | NM_173201.5 | c.2463_2464dupCC | p.Arg822ProfsTer50 | frameshift_variant | Exon 17 of 22 | NP_775293.1 | ||
| ATP2A1 | NM_001286075.2 | c.2088_2089dupCC | p.Arg697ProfsTer50 | frameshift_variant | Exon 15 of 21 | NP_001273004.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATP2A1 | ENST00000395503.9 | c.2463_2464dupCC | p.Arg822ProfsTer50 | frameshift_variant | Exon 17 of 23 | 1 | NM_004320.6 | ENSP00000378879.5 | ||
| ATP2A1 | ENST00000357084.7 | c.2463_2464dupCC | p.Arg822ProfsTer50 | frameshift_variant | Exon 17 of 22 | 2 | ENSP00000349595.3 | |||
| ATP2A1 | ENST00000536376.5 | c.2088_2089dupCC | p.Arg697ProfsTer50 | frameshift_variant | Exon 15 of 21 | 2 | ENSP00000443101.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461154Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 726866 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
3
AN:
1461154
Hom.:
Cov.:
33
AF XY:
AC XY:
3
AN XY:
726866
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33472
American (AMR)
AF:
AC:
0
AN:
44714
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26128
East Asian (EAS)
AF:
AC:
0
AN:
39696
South Asian (SAS)
AF:
AC:
0
AN:
86240
European-Finnish (FIN)
AF:
AC:
2
AN:
53244
Middle Eastern (MID)
AF:
AC:
0
AN:
5760
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111534
Other (OTH)
AF:
AC:
1
AN:
60366
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.242
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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