2-71602794-A-G
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_001130987.2(DYSF):āc.3946A>Gā(p.Ile1316Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00624 in 1,613,374 control chromosomes in the GnomAD database, including 49 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). Synonymous variant affecting the same amino acid position (i.e. I1316I) has been classified as Likely benign.
Frequency
Consequence
NM_001130987.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.3946A>G | p.Ile1316Val | missense_variant | 36/56 | ENST00000410020.8 | |
DYSF | NM_003494.4 | c.3892A>G | p.Ile1298Val | missense_variant | 36/55 | ENST00000258104.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.3946A>G | p.Ile1316Val | missense_variant | 36/56 | 1 | NM_001130987.2 | A1 | |
DYSF | ENST00000258104.8 | c.3892A>G | p.Ile1298Val | missense_variant | 36/55 | 1 | NM_003494.4 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00457 AC: 695AN: 152140Hom.: 3 Cov.: 32
GnomAD3 exomes AF: 0.00458 AC: 1141AN: 248942Hom.: 7 AF XY: 0.00471 AC XY: 634AN XY: 134732
GnomAD4 exome AF: 0.00642 AC: 9377AN: 1461116Hom.: 46 Cov.: 31 AF XY: 0.00636 AC XY: 4619AN XY: 726746
GnomAD4 genome AF: 0.00456 AC: 695AN: 152258Hom.: 3 Cov.: 32 AF XY: 0.00450 AC XY: 335AN XY: 74474
ClinVar
Submissions by phenotype
not provided Benign:5
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | DYSF: BP4, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 28, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 10, 2020 | This variant is associated with the following publications: (PMID: 24123366, 25898921, 9731526, 25525159, 11468312, 21816046, 22995991, 16934466, 20544924, 30919934, 32528171) - |
Autosomal recessive limb-girdle muscular dystrophy type 2B Pathogenic:1Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 14, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 1998 | - - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 10, 2020 | - - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 09, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 18, 2022 | Variant summary: DYSF c.3892A>G (p.Ile1298Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0046 in 248942 control chromosomes, predominantly at a frequency of 0.0072 within the Non-Finnish European subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.35 fold of the estimated maximal expected allele frequency for a pathogenic variant in DYSF causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.0031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3892A>G has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (examples: Liu_1998, ten Dam_2019). These reports do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. Nine 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: seven classified as likely benign/benign while two classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign. - |
Miyoshi muscular dystrophy 1 Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 1998 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 14, 2021 | - - |
Qualitative or quantitative defects of dysferlin Benign:1Other:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Distal myopathy with anterior tibial onset Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 14, 2021 | - - |
DYSF-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at