chr11-65182922-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM2BP4_ModerateBS1_Supporting
The NM_005186.4(CAPN1):c.221G>A(p.Gly74Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00033 in 1,612,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_005186.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000309 AC: 47AN: 152136Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000330 AC: 81AN: 245290Hom.: 0 AF XY: 0.000383 AC XY: 51AN XY: 133134
GnomAD4 exome AF: 0.000332 AC: 485AN: 1460038Hom.: 0 Cov.: 31 AF XY: 0.000370 AC XY: 269AN XY: 726152
GnomAD4 genome AF: 0.000309 AC: 47AN: 152254Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26AN XY: 74444
ClinVar
Submissions by phenotype
Autosomal recessive spastic paraplegia type 76 Uncertain:3
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spastic paraplegia 76 (MIM#616907). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (89 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated peptidase C2 domain (NCBI, PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. The variant has previously been reported as likely pathogenic in one compound heterozygous individual with hereditary spastic paraplegia, however the variant was in cis with another missense that was also considered to be likely pathogenic (LOVD, PMID: 28566166). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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not provided Uncertain:2
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 74 of the CAPN1 protein (p.Gly74Asp). This variant is present in population databases (rs201318945, gnomAD 0.07%). This missense change has been observed in individual(s) with spastic paraplegia (PMID: 28566166). ClinVar contains an entry for this variant (Variation ID: 1510947). 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: "Probably 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. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at