rs868448815
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_004320.6(ATP2A1):c.1466G>A(p.Arg489Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,990 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 (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000024 ( 0 hom. )
Consequence
ATP2A1
NM_004320.6 missense
NM_004320.6 missense
Scores
11
7
1
Clinical Significance
Conservation
PhyloP100: 10.0
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 Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a binding_site (size 0) in uniprot entity AT2A1_HUMAN
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.85
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP2A1 | NM_004320.6 | c.1466G>A | p.Arg489Gln | missense_variant | 13/23 | ENST00000395503.9 | |
ATP2A1 | NM_173201.5 | c.1466G>A | p.Arg489Gln | missense_variant | 13/22 | ||
ATP2A1 | NM_001286075.2 | c.1091G>A | p.Arg364Gln | missense_variant | 11/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP2A1 | ENST00000395503.9 | c.1466G>A | p.Arg489Gln | missense_variant | 13/23 | 1 | NM_004320.6 | P4 | |
ATP2A1 | ENST00000357084.7 | c.1466G>A | p.Arg489Gln | missense_variant | 13/22 | 2 | A1 | ||
ATP2A1 | ENST00000536376.5 | c.1091G>A | p.Arg364Gln | missense_variant | 11/21 | 2 | |||
ATP2A1 | ENST00000564732.1 | c.*109G>A | 3_prime_UTR_variant, NMD_transcript_variant | 5/7 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152112Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251462Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135900
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GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461878Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18AN XY: 727240
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152112Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74298
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Brody myopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 24, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 27, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 489 of the ATP2A1 protein (p.Arg489Gln). This variant is present in population databases (no rsID available, gnomAD 0.02%). 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: 446877). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 09, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;D;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0231);Loss of MoRF binding (P = 0.0231);.;
MVP
MPC
ClinPred
D
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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