rs148055736
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6BP7
The ENST00000410020.8(DYSF):c.4542C>T(p.Ile1514=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,610,692 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.00035 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000083 ( 0 hom. )
Consequence
DYSF
ENST00000410020.8 synonymous
ENST00000410020.8 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.285
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 Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.33).
BP6
Variant 2-71643979-C-T is Benign according to our data. Variant chr2-71643979-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259079.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
BP7
Synonymous conserved (PhyloP=-0.285 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.4542C>T | p.Ile1514= | synonymous_variant | 42/56 | ENST00000410020.8 | NP_001124459.1 | |
DYSF | NM_003494.4 | c.4425C>T | p.Ile1475= | synonymous_variant | 41/55 | ENST00000258104.8 | NP_003485.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.4542C>T | p.Ile1514= | synonymous_variant | 42/56 | 1 | NM_001130987.2 | ENSP00000386881 | A1 | |
DYSF | ENST00000258104.8 | c.4425C>T | p.Ile1475= | synonymous_variant | 41/55 | 1 | NM_003494.4 | ENSP00000258104 | A1 |
Frequencies
GnomAD3 genomes AF: 0.000348 AC: 53AN: 152120Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000102 AC: 25AN: 245956Hom.: 0 AF XY: 0.0000904 AC XY: 12AN XY: 132760
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GnomAD4 exome AF: 0.0000830 AC: 121AN: 1458454Hom.: 0 Cov.: 32 AF XY: 0.0000717 AC XY: 52AN XY: 725092
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GnomAD4 genome AF: 0.000355 AC: 54AN: 152238Hom.: 0 Cov.: 33 AF XY: 0.000390 AC XY: 29AN XY: 74424
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Qualitative or quantitative defects of dysferlin Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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, 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 24, 2015 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2B Benign:1
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
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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