rs1057521141
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_001130987.2(DYSF):c.6025C>T(p.Pro2009Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P2009P) has been classified as Likely benign.
Frequency
Consequence
NM_001130987.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.6025C>T | p.Pro2009Ser | missense_variant | 53/56 | ENST00000410020.8 | |
DYSF | NM_003494.4 | c.5908C>T | p.Pro1970Ser | missense_variant | 52/55 | ENST00000258104.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.6025C>T | p.Pro2009Ser | missense_variant | 53/56 | 1 | NM_001130987.2 | A1 | |
DYSF | ENST00000258104.8 | c.5908C>T | p.Pro1970Ser | missense_variant | 52/55 | 1 | NM_003494.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461782Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4AN XY: 727190
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2B Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2021 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Dec 07, 2017 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 29, 2016 | The P1970S variant in the DYSF gene has been reported previously in association with limb girdle muscular dystrophy type 2B (LGMD2B) and absence of dysferlin on muscle biopsy by immunohistochemistry or Western blot (Krahn et al., 2009; Walsh et al., 2011). The P1970S variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P1970S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The P1970S variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. - |
Miyoshi muscular dystrophy 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 15, 2022 | - - |
Qualitative or quantitative defects of dysferlin Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 23, 2021 | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DYSF protein function. This variant has been observed in individual(s) with limb-girdle muscular dystrophy type 2B (PMID: 18853459, 27666772, 21484829). ClinVar contains an entry for this variant (Variation ID: 381677). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 1970 of the DYSF protein (p.Pro1970Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at