rs201892814
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_000070.3(CAPN3):c.1746-20C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,612,376 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: ๐ 0.0031 ( 1 hom., cov: 32)
Exomes ๐: 0.0031 ( 14 hom. )
Consequence
CAPN3
NM_000070.3 intron
NM_000070.3 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.0590
Genes affected
CAPN3 (HGNC:1480): (calpain 3) Calpain, a heterodimer consisting of a large and a small subunit, is a major intracellular protease, although its function has not been well established. This gene encodes a muscle-specific member of the calpain large subunit family that specifically binds to titin. Mutations in this gene are associated with limb-girdle muscular dystrophies type 2A. Alternate promoters and alternative splicing result in multiple transcript variants encoding different isoforms and some variants are ubiquitously expressed. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BS2
?
High Homozygotes in GnomAdExome at 3 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.1746-20C>G | intron_variant | ENST00000397163.8 | |||
CAPN3 | NM_024344.2 | c.1746-20C>G | intron_variant | ||||
CAPN3 | NM_173087.2 | c.1602-20C>G | intron_variant | ||||
CAPN3 | NM_173088.2 | c.210-20C>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.1746-20C>G | intron_variant | 1 | NM_000070.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00309 AC: 470AN: 152174Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.00315 AC: 791AN: 251486Hom.: 3 AF XY: 0.00324 AC XY: 441AN XY: 135918
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GnomAD4 exome AF: 0.00311 AC: 4534AN: 1460084Hom.: 14 Cov.: 30 AF XY: 0.00312 AC XY: 2268AN XY: 726476
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:4Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 18, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 17, 2020 | - - |
not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 06, 2018 | This variant is associated with the following publications: (PMID: 18055493, 28877744, 20635405, 17994539, 17979987, 17157502, 16141003, 16411092, 15351423, 16372320, 27447704, 27708273, 26886200, 27884173, 26301378, 28602176, 25135358, 18854869, 30028523, 30919934, 31788660, 32403337, 31127727) - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | CAPN3: BS1, BS2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | May 31, 2023 | PP4, PS3 - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 06, 2022 | Variant summary: CAPN3 c.1746-20C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. This is confirmed by one study reporting no impact on splicing (example, Krahn_2007). In another study. the average value for amount of CAPN3 transcripts relative to three housekeeping genes using CAPN3 mRNA of a patient without splice variant as calibrator, showed the levels of transcript in a patient with this variant in a compound heterozygous genotype did not differ significantly from the control values (example, Stehlikova_2007). The variant allele was found at a frequency of 0.0031 in 251486 control chromosomes, predominantly at a frequency of 0.0043 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. This variant is among those re-classified as benign based on lack of phenotype in homozygotes (ACMG BS2-only variants) (example, Abouelhoda_2016). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1746-20C>G has been reported in the literature as a non-informative genotype in numerous compound heterozygous patients undergoing testing for limb girdle muscular dystrophy via panel/exome/single gene analysis (example, Piluso_2005, Krahn_2007, Stehlikova_2007, Nascimbeni_2010, Avila_2015, Harris_2017, Reddy_2017). In at-least one of these reports it was found to co-occur in cis with a different allele (c.1745+4_1745+7delAGTG) that was characterized by complementary DNA analysis as having a pathogenic outcome (example, Krahn_2007). These report(s) do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy type 2A, Autosomal Recessive. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 23, 2016 | - - |
Paresthesia;C0149931:Migraine;C0240914:Positive Romberg sign;C0241005:Elevated circulating creatine kinase concentration;C0311394:Difficulty walking;C4021727:EMG: neuropathic changes;C4022625:Absent muscle fiber calpain-3;C4082951:Progressive spinal muscular atrophy Pathogenic:1
Pathogenic, flagged submission | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Autosomal recessive limb-girdle muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 02, 2023 | The heterozygous c.1746-20C>G variant in CAPN3 was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 166786) in one individual with limb girdle muscular dystrophy (Broad Institute Rare Genomes Project). Familial exome analysis revealed that this variant was in trans with a pathogenic variant (ClinVar Variation ID: 166786). The c.1746-20C>G variant in CAPN3 has been previously reported in 19 individuals with autosomal recessive limb-girdle muscular dystrophy 1 (PMID: 30028523, PMID: 27708273, PMID: 27447704, PMID: 28877744, PMID: 28602176, PMID: 26886200, PMID: 18854869, PMID: 18055493, PMID: 16141003, PMID: 17994539, PMID: 16411092, PMID: 17157502, PMID: 17979987) and segregated with disease in two affected individuals from one family (PMID: 27708273), but has been identified in 1.1% (122/10614) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs201892814). This variant has been seen in the general population, in a heterozygous state, at greater rate than expected for disorder. This variant has also been reported in ClinVar (Variation ID: 92408) and has conflicting interpretations. Of the 19 affected individuals reported (PMID: 30028523, PMID: 27708273, PMID: 27447704, PMID: 28877744, PMID: 28602176, PMID: 26886200, PMID: 18854869, PMID: 18055493, PMID: 16141003, PMID: 17994539, PMID: 16411092, PMID: 17157502, PMID: 17979987), one was a homozygote (PMID: 16411092), six were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 18854869, ClinVar Variation ID: 17621, ClinVar Variation ID: 282783; PMID: 26886200, ClinVar Variation ID: 282783; PMID: 28877744, ClinVar Variation ID: 197624; PMID: 2744770, ClinVar Variation ID: 282783, ClinVar Variation ID: 166786), three were presumed compound heterozygotes who carried pathogenic or likely pathogenic variants in unknown phase (PMID: 17157502, ClinVar Variation ID: 166786; PMID: 28602176, PMID: 30028523, ClinVar Variation ID: 813980) and four were compound heterozygotes who carried variants of uncertain significance in trans (PMID: 17994539, PMID: 18854869; PMID: 27708273), which increases the likelihood that the c.1746-20C>G variant is pathogenic. RT-PCR analyses performed on affected tissue are conflicting regarding whether this variant impacts splicing (PMID: 17979987, PMID: 20635405). This variant is located in the 3โรรด splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the c.1746-20C>G variant is uncertain. ACMG/AMP Criteria applied: PM3_VeryStrong, BS1, PP1_moderate (Richards 2015). - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
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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