rs387907036
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate
The NM_022489.4(INF2):c.312C>G(p.Cys104Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C104F) has been classified as Pathogenic.
Frequency
Consequence
NM_022489.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
INF2 | NM_022489.4 | c.312C>G | p.Cys104Trp | missense_variant | 2/23 | ENST00000392634.9 | |
INF2 | NM_001031714.4 | c.312C>G | p.Cys104Trp | missense_variant | 2/22 | ||
INF2 | NM_032714.3 | c.312C>G | p.Cys104Trp | missense_variant | 2/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
INF2 | ENST00000392634.9 | c.312C>G | p.Cys104Trp | missense_variant | 2/23 | 5 | NM_022489.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD4 exome Cov.: 35
GnomAD4 genome ? Cov.: 34
ClinVar
Submissions by phenotype
Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 14, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys104 amino acid residue in INF2. Other variant(s) that disrupt this residue have been observed in individuals with INF2-related conditions (PMID: 22187985, 30373780), which suggests that this may be a clinically significant amino acid residue. 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 INF2 protein function. ClinVar contains an entry for this variant (Variation ID: 30866). This missense change has been observed in individuals with clinical features of Charcot-Marie-Tooth disease and Charcot-Marie-Tooth disease and focal segmental glomerulosclerosis (PMID: 22187985, 29653220; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 104 of the INF2 protein (p.Cys104Trp). - |
Charcot-Marie-Tooth disease dominant intermediate E Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 22, 2011 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at