rs794727697
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM4_SupportingPP5_Very_Strong
The NM_000070.3(CAPN3):c.759_761delGAA(p.Lys254del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000062 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
NM_000070.3 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.759_761delGAA | p.Lys254del | disruptive_inframe_deletion | Exon 5 of 24 | ENST00000397163.8 | NP_000061.1 | |
CAPN3 | NM_024344.2 | c.759_761delGAA | p.Lys254del | disruptive_inframe_deletion | Exon 5 of 23 | NP_077320.1 | ||
CAPN3 | NM_173087.2 | c.759_761delGAA | p.Lys254del | disruptive_inframe_deletion | Exon 5 of 21 | NP_775110.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.759_761delGAA | p.Lys254del | disruptive_inframe_deletion | Exon 5 of 24 | 1 | NM_000070.3 | ENSP00000380349.3 | ||
ENSG00000258461 | ENST00000495723.1 | n.*555_*557delGAA | non_coding_transcript_exon_variant | Exon 9 of 26 | 2 | ENSP00000492063.1 | ||||
ENSG00000258461 | ENST00000495723.1 | n.*555_*557delGAA | 3_prime_UTR_variant | Exon 9 of 26 | 2 | ENSP00000492063.1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152106Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251418Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135870
GnomAD4 exome AF: 0.0000629 AC: 92AN: 1461882Hom.: 0 AF XY: 0.0000688 AC XY: 50AN XY: 727246
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74306
ClinVar
Submissions by phenotype
not provided Pathogenic:5
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -
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CAPN3: PM3:Very Strong, PM2, PM4:Supporting -
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In-frame deletion of 1 amino acid in a non-repeat region predicted to critically alter the protein; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22622166, 20694146, 34720847, 26810512, 16141003, 10330340, 28300015, 12461690, 27447704, 16344536, 18334579, 18563459, 30564623, 30919934, 31980526, 33741228, 32528171, 18055493) -
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:3
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This variant, c.759_761del, results in the deletion of 1 amino acid(s) of the CAPN3 protein (p.Lys254del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs760168012, gnomAD 0.01%). This variant has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 10330340, 16141003, 18055493, 18334579, 18563459, 20694146, 22622166). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 197624). For these reasons, this variant has been classified as Pathogenic. -
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Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
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Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1
The NM_000070.3: c.759_761del variant in CAPN3, which is also known as c.756_758del, is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region, p.(Lys254del) (PM4). This variant has been detected in at least 11 unrelated individuals with limb girdle muscular dystrophy (PMID: 26886200, 10330340, 16141003, 18055493, 30564623, 12461690, 35731190), including in a homozygous state in one case (0.5 pts; PMID: 18055493), confirmed in trans with a pathogenic variant in three cases (c.1468C>T p.(Arg490Trp), 1.0 pt, PMID: 12461690; c.1746-20C>G, 2.0 pts, PMID: 35731190), and in unknown phase with a pathogenic variant in one case (c.1468C>T p.(Arg490Trp), 0.5 pts, PMID: 18055493) (PM3_Very Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PP4). The filtering allele frequency of the variant is 0.0001933 for European (non-Finnish) genome alleles in gnomAD v3.1.2 (the upper threshold of the 95% CI of 7/68016), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM4, PM3_Very Strong, PP4. -
Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
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See cases Pathogenic:1
ACMG classification criteria: PS3, PS4, PM4 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at