chr2-71598577-C-T
Variant summary
Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1
This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.3534C>T p.(Ile1178=) variant in DYSF, which is also known as NM_001130987.2: c.3588C>T (p.Ile1196=), is a synonymous (silent) variant that is not located in a splice region (outside of the first and the last 3 bases of the exon). The filtering allele frequency for this variant is 0.008874 in gnomAD v4.1.0 (the lower threshold of the 95% CI of 10642/1180038 European (non-Finnish) chromosomes), which is higher than the VCEP threshold of 0.003 (BA1). This variant was detected in a heterozygous state in one individual with suspected LGMD and absent dysferlin expression by blood monocyte assay. No second variant in DYSF was identified, and this individual also had two variants in DNAJB6 (PMID:25493284, 36983702). The SpliceAI prediction score for this variant is 0.27, which is greater than the VCEP threshold of <0.05 (BP4 not met). However, RNASeq data showed this variant does not affect splicing (PMID:36983702). In summary, this variant meets the criteria to be classified as Benign 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; 05/19/2025): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA152665/MONDO:0015152/180
Frequency
Consequence
NM_001130987.2 synonymous
Scores
Clinical Significance
Conservation
Publications
- autosomal recessive limb-girdle muscular dystrophyInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- neuromuscular disease caused by qualitative or quantitative defects of dysferlinInheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
- autosomal recessive limb-girdle muscular dystrophy type 2BInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
- distal myopathy with anterior tibial onsetInheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- congenital myopathy, Paradas typeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Miyoshi myopathyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Benign. The variant received -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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DYSF | NM_001130987.2 | c.3588C>T | p.Ile1196Ile | synonymous_variant | Exon 33 of 56 | ENST00000410020.8 | NP_001124459.1 | |
DYSF | NM_003494.4 | c.3534C>T | p.Ile1178Ile | synonymous_variant | Exon 33 of 55 | ENST00000258104.8 | NP_003485.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.3588C>T | p.Ile1196Ile | synonymous_variant | Exon 33 of 56 | 1 | NM_001130987.2 | ENSP00000386881.3 | ||
DYSF | ENST00000258104.8 | c.3534C>T | p.Ile1178Ile | synonymous_variant | Exon 33 of 55 | 1 | NM_003494.4 | ENSP00000258104.3 |
Frequencies
GnomAD3 genomes AF: 0.00614 AC: 934AN: 152218Hom.: 6 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.00666 AC: 1673AN: 251142 AF XY: 0.00678 show subpopulations
GnomAD4 exome AF: 0.00787 AC: 11498AN: 1461862Hom.: 53 Cov.: 32 AF XY: 0.00790 AC XY: 5747AN XY: 727226 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00613 AC: 934AN: 152336Hom.: 6 Cov.: 33 AF XY: 0.00584 AC XY: 435AN XY: 74504 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not specified Benign:4
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This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
not provided Benign:3
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DYSF: BS2 -
Neuromuscular disease caused by qualitative or quantitative defects of dysferlin Uncertain:1Benign:1
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Limb-girdle muscular dystrophy, recessive Uncertain:1
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Miyoshi myopathy Uncertain:1
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Autosomal recessive limb-girdle muscular dystrophy Benign:1
The NM_003494.4: c.3534C>T p.(Ile1178=) variant in DYSF, which is also known as NM_001130987.2: c.3588C>T (p.Ile1196=), is a synonymous (silent) variant that is not located in a splice region (outside of the first and the last 3 bases of the exon). The filtering allele frequency for this variant is 0.008874 in gnomAD v4.1.0 (the lower threshold of the 95% CI of 10642/1180038 European (non-Finnish) chromosomes), which is higher than the VCEP threshold of 0.003 (BA1). This variant was detected in a heterozygous state in one individual with suspected LGMD and absent dysferlin expression by blood monocyte assay. No second variant in DYSF was identified, and this individual also had two variants in DNAJB6 (PMID: 25493284, 36983702). The SpliceAI prediction score for this variant is 0.27, which is greater than the VCEP threshold of <0.05 (BP4 not met). However, RNASeq data showed this variant does not affect splicing (PMID: 36983702). In summary, this variant meets the criteria to be classified as Benign 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; 05/19/2025): BA1. -
Autosomal recessive limb-girdle muscular dystrophy type 2B Benign:1
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Miyoshi muscular dystrophy 1 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at