rs36122356
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_001130987.2(DYSF):c.1038C>T(p.His346=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0569 in 1,613,280 control chromosomes in the GnomAD database, including 2,957 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.065 ( 395 hom., cov: 32)
Exomes 𝑓: 0.056 ( 2562 hom. )
Consequence
DYSF
NM_001130987.2 synonymous
NM_001130987.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -3.59
Genes affected
DYSF (HGNC:3097): (dysferlin) The protein encoded by this gene belongs to the ferlin family and is a skeletal muscle protein found associated with the sarcolemma. It is involved in muscle contraction and contains C2 domains that play a role in calcium-mediated membrane fusion events, suggesting that it may be involved in membrane regeneration and repair. In addition, the protein encoded by this gene binds caveolin-3, a skeletal muscle membrane protein which is important in the formation of caveolae. Specific mutations in this gene have been shown to cause autosomal recessive limb girdle muscular dystrophy type 2B (LGMD2B) as well as Miyoshi myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.69).
BP6
?
Variant 2-71520793-C-T is Benign according to our data. Variant chr2-71520793-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 94369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71520793-C-T is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-3.59 with no splicing effect.
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0936 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.1038C>T | p.His346= | synonymous_variant | 12/56 | ENST00000410020.8 | |
DYSF | NM_003494.4 | c.942C>T | p.His314= | synonymous_variant | 11/55 | ENST00000258104.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.1038C>T | p.His346= | synonymous_variant | 12/56 | 1 | NM_001130987.2 | A1 | |
DYSF | ENST00000258104.8 | c.942C>T | p.His314= | synonymous_variant | 11/55 | 1 | NM_003494.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0649 AC: 9863AN: 152022Hom.: 395 Cov.: 32
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GnomAD3 exomes AF: 0.0565 AC: 14197AN: 251450Hom.: 515 AF XY: 0.0580 AC XY: 7879AN XY: 135902
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GnomAD4 exome AF: 0.0560 AC: 81883AN: 1461140Hom.: 2562 Cov.: 32 AF XY: 0.0569 AC XY: 41336AN XY: 726890
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GnomAD4 genome ? AF: 0.0649 AC: 9869AN: 152140Hom.: 395 Cov.: 32 AF XY: 0.0637 AC XY: 4739AN XY: 74390
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:5
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 13, 2015 | p.His346His in exon 12 of DYSF: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 9.0% (395/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs36122356). - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 15, 2012 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 08, 2016 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | - | 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. - |
Qualitative or quantitative defects of dysferlin Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Limb-girdle muscular dystrophy, recessive Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 17, 2017 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2B Benign:1
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Miyoshi muscular dystrophy 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 10, 2021 | - - |
Miyoshi myopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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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