chr16-28878672-A-G
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_004320.6(ATP2A1):āc.1A>Gā(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,596,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.000013 ( 0 hom. )
Consequence
ATP2A1
NM_004320.6 start_lost
NM_004320.6 start_lost
Scores
6
9
1
Clinical Significance
Conservation
PhyloP100: 8.15
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP2A1 | NM_004320.6 | c.1A>G | p.Met1? | start_lost | 1/23 | ENST00000395503.9 | |
ATP2A1 | NM_173201.5 | c.1A>G | p.Met1? | start_lost | 1/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP2A1 | ENST00000395503.9 | c.1A>G | p.Met1? | start_lost | 1/23 | 1 | NM_004320.6 | P4 | |
ATP2A1-AS1 | ENST00000691192.2 | n.1265T>C | non_coding_transcript_exon_variant | 1/1 | |||||
ATP2A1 | ENST00000357084.7 | c.1A>G | p.Met1? | start_lost | 1/22 | 2 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000901 AC: 2AN: 222054Hom.: 0 AF XY: 0.0000167 AC XY: 2AN XY: 119650
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GnomAD4 exome AF: 0.0000132 AC: 19AN: 1443988Hom.: 0 Cov.: 31 AF XY: 0.0000195 AC XY: 14AN XY: 716680
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74326
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Brody myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 04, 2022 | This sequence change affects the initiator methionine of the ATP2A1 mRNA. The next in-frame methionine is located at codon 126. This variant is present in population databases (rs368689264, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with ATP2A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1044543). 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
P;P
Vest4
MVP
ClinPred
D
GERP RS
Varity_R
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at