rs766936914
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001130987.2(DYSF):c.1350delC(p.Phe451fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
DYSF
NM_001130987.2 frameshift
NM_001130987.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.264
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-71528367-AC-A is Pathogenic according to our data. Variant chr2-71528367-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 551669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71528367-AC-A is described in Lovd as [Pathogenic]. Variant chr2-71528367-AC-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.1350delC | p.Phe451fs | frameshift_variant | 14/56 | ENST00000410020.8 | NP_001124459.1 | |
DYSF | NM_003494.4 | c.1254delC | p.Phe419fs | frameshift_variant | 13/55 | ENST00000258104.8 | NP_003485.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.1350delC | p.Phe451fs | frameshift_variant | 14/56 | 1 | NM_001130987.2 | ENSP00000386881.3 | ||
DYSF | ENST00000258104.8 | c.1254delC | p.Phe419fs | frameshift_variant | 13/55 | 1 | NM_003494.4 | ENSP00000258104.3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251376Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135860
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461836Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727206
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GnomAD4 genome Cov.: 33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 04, 2017 | - - |
Miyoshi muscular dystrophy 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 10, 2023 | - - |
Qualitative or quantitative defects of dysferlin Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 14, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 551669). This variant is also known as Pro418ProfsX123. This premature translational stop signal has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy and/or dysferlinopathy (PMID: 17994539, 27647186). This variant is present in population databases (rs766936914, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Phe419Leufs*41) in the DYSF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). - |
Computational scores
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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