NM_000070.3:c.440G>A
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.
The NM_000070.3(CAPN3):c.440G>A(p.Arg147Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R147L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000070.3 missense
Scores
Clinical Significance
Conservation
Publications
- autosomal recessive limb-girdle muscular dystrophyInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- autosomal recessive limb-girdle muscular dystrophy type 2AInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
- muscular dystrophy, limb-girdle, autosomal dominant 4Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- muscular dystrophy, limb-girdle, autosomal dominantInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.440G>A | p.Arg147Gln | missense_variant | Exon 3 of 24 | ENST00000397163.8 | NP_000061.1 | |
CAPN3 | NM_024344.2 | c.440G>A | p.Arg147Gln | missense_variant | Exon 3 of 23 | NP_077320.1 | ||
CAPN3 | NM_173087.2 | c.440G>A | p.Arg147Gln | missense_variant | Exon 3 of 21 | NP_775110.1 | ||
LOC105370794 | XR_932178.3 | n.-196C>T | upstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.440G>A | p.Arg147Gln | missense_variant | Exon 3 of 24 | 1 | NM_000070.3 | ENSP00000380349.3 | ||
ENSG00000258461 | ENST00000495723.1 | n.*236G>A | non_coding_transcript_exon_variant | Exon 7 of 26 | 2 | ENSP00000492063.1 | ||||
ENSG00000258461 | ENST00000495723.1 | n.*236G>A | 3_prime_UTR_variant | Exon 7 of 26 | 2 | ENSP00000492063.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152112Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000278 AC: 7AN: 251430 AF XY: 0.0000221 show subpopulations
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461842Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727234 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152112Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74304 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Uncertain:2
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 147 of the CAPN3 protein (p.Arg147Gln). This variant is present in population databases (rs139671324, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 17994539, 33337384). ClinVar contains an entry for this variant (Variation ID: 552291). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CAPN3 protein function with a negative predictive value of 80%. 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. -
Muscular dystrophy, limb-girdle, autosomal dominant 4 Uncertain:1
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Loss of function is known mechanism of disease in this gene and are associated with autosomal recessive limb-girdle muscular dystrophy 1 (MIM#253600), while dominant-negative is the suggested mechanism for autosomal dominant limb-girdle muscular dystrophy 4 (MIM#618129) (PMID: 2725975, 28881388, 32342993). (I) 0108 - This gene is associated with both recessive and dominant disease. AD inheritance is rare, however emerging literature reports both missense and small in-frame deletion segregating with disease in families. In addition, AD variants are associated with milder and later-onset phenotypes (PMID: 27259757, 28881388, 32557990, 32896923, 32342993). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 7 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 catalytic domain (NCBI, PDB). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Arg147Pro) was identified in a compound heterozygous state in a patient with limb-girdle muscular dystrophy. It has also been reported in a heterozygous state where the second allele was not identified (PMID: 17596655, 10567047, 27363342). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported in a compound heterozygote individual with autosomal recessive limb-girdle muscular dystrophy 1 (MIM#253600). However, it has been classified as a VUS by a diagnostic laboratory in ClinVar (ClinVar; PMID: 17994539). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not specified Uncertain:1
Variant summary: CAPN3 c.440G>A (p.Arg147Gln) results in a conservative amino acid change located in the Peptidase C2, calpain, catalytic domain (IPR001300) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251430 control chromosomes (gnomAD). c.440G>A has been reported in the literature as a compound heterozygous genotype in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Pathak_2021 and Guglieri_2008). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
not provided Uncertain:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32896923, 27259757, 28881388, 33337384, 32557990, 32342993, 27363342, 17596655, 10567047, 2725975, 17994539) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at