rs1057516051
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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):βc.4941delβ(p.Lys1648ArgfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000186 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 0.0000014 ( 0 hom. )
Consequence
DYSF
NM_001130987.2 frameshift
NM_001130987.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.90
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 2-71660586-AG-A is Pathogenic according to our data. Variant chr2-71660586-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 369690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71660586-AG-A is described in Lovd as [Pathogenic]. Variant chr2-71660586-AG-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.4941del | p.Lys1648ArgfsTer4 | frameshift_variant | 45/56 | ENST00000410020.8 | |
DYSF | NM_003494.4 | c.4824del | p.Lys1609ArgfsTer4 | frameshift_variant | 44/55 | ENST00000258104.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.4941del | p.Lys1648ArgfsTer4 | frameshift_variant | 45/56 | 1 | NM_001130987.2 | A1 | |
DYSF | ENST00000258104.8 | c.4824del | p.Lys1609ArgfsTer4 | frameshift_variant | 44/55 | 1 | NM_003494.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461784Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727194
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74340
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Proximal muscle weakness Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Institute of Human Genetics, University of Wuerzburg | - | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 22, 2017 | - - |
Miyoshi muscular dystrophy 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 17, 2024 | - - |
Qualitative or quantitative defects of dysferlin Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 28, 2023 | This sequence change creates a premature translational stop signal (p.Lys1609Argfs*4) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with limb-girdle muscular dystrophy (LGMD) (PMID: 29970176). ClinVar contains an entry for this variant (Variation ID: 369690). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at