2-71665253-C-T
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_001130987.2(DYSF):c.5266C>T(p.Arg1756Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000835 in 1,614,180 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1756Q) has been classified as Likely benign.
Frequency
Consequence
NM_001130987.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.5266C>T | p.Arg1756Trp | missense_variant | 47/56 | ENST00000410020.8 | |
DYSF | NM_003494.4 | c.5149C>T | p.Arg1717Trp | missense_variant | 46/55 | ENST00000258104.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.5266C>T | p.Arg1756Trp | missense_variant | 47/56 | 1 | NM_001130987.2 | A1 | |
DYSF | ENST00000258104.8 | c.5149C>T | p.Arg1717Trp | missense_variant | 46/55 | 1 | NM_003494.4 | A1 |
Frequencies
GnomAD3 genomes AF: 0.000677 AC: 103AN: 152184Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000517 AC: 130AN: 251468Hom.: 0 AF XY: 0.000545 AC XY: 74AN XY: 135900
GnomAD4 exome AF: 0.000852 AC: 1246AN: 1461878Hom.: 2 Cov.: 32 AF XY: 0.000825 AC XY: 600AN XY: 727240
GnomAD4 genome AF: 0.000670 AC: 102AN: 152302Hom.: 1 Cov.: 33 AF XY: 0.000671 AC XY: 50AN XY: 74480
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 01, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 14, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | DYSF: BP4 - |
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 03, 2022 | Variant summary: DYSF c.5149C>T (p.Arg1717Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00052 in 251468 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in DYSF causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.00052 vs 0.0031), allowing no conclusion about variant significance. c.5149C>T has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Cacciottolo_2011, Nallamilli_2018). These reports do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 05, 2017 | - - |
Qualitative or quantitative defects of dysferlin Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Dec 11, 2018 | The DYSF c.5149C>T (p.Arg1717Trp) variant is a missense variant which has been reported in one individual with dysferlin deficiency in a compound heterozygous state with a second missense variant (Cacciottolo et al. 2011). The p.Arg1717Trp variant was absent from 1000 controls and is reported at a frequency of 0.00116 in the European American population of the Exome Sequencing Project. Based on the evidence, the p.Arg1717Trp variant is classified as a variant of unknown significance but suspicious for pathogenicity for dysferlinopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2B Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at