chr2-71516241-CG-C
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PM2PP3_ModeratePP5_Very_Strong
The NM_001130987.2(DYSF):c.951+1del variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,924 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001130987.2 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.951+1del | frameshift_variant, splice_region_variant | 9/56 | ENST00000410020.8 | ||
DYSF | NM_003494.4 | c.855+1del | frameshift_variant, splice_region_variant | 8/55 | ENST00000258104.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.951+1del | frameshift_variant, splice_region_variant | 9/56 | 1 | NM_001130987.2 | A1 | ||
DYSF | ENST00000258104.8 | c.855+1del | frameshift_variant, splice_region_variant | 8/55 | 1 | NM_003494.4 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152228Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251384Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135888
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461696Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 727178
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74368
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2B Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 23, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2008 | - - |
Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 13, 2024 | Variant summary: DYSF c.855+1delG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. Three predict the variant creates a 5' donor site. At least one publication reports experimental evidence that this variant mRNA was absent in patient cells (Wenzel_2006), suggesting it undergoes nonsense mediated decay. The variant allele was found at a frequency of 8e-06 in 251384 control chromosomes (gnomAD). c.855+1delG has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Wenzel_2006, Krahn_2009). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16705711, 18853459). ClinVar contains an entry for this variant (Variation ID: 6684). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Miyoshi muscular dystrophy 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 21, 2024 | - - |
Qualitative or quantitative defects of dysferlin Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 20, 2023 | This sequence change affects a splice site in intron 8 of the DYSF gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). This variant is present in population databases (rs786200898, gnomAD 0.009%). Disruption of this splice site has been observed in individual(s) with dysferlin deficient muscular dystrophy (PMID: 16010686, 18306167, 19528035). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6684). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at