chr11-2159886-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000207.3(INS):c.299G>A(p.Cys100Tyr) variant causes a missense change. 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 Uncertain significance (★).
Frequency
Consequence
NM_000207.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 35
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 2443150). This variant has not been reported in the literature in individuals affected with INS-related conditions. This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 100 of the INS protein (p.Cys100Tyr). -
DNA sequence analysis of the INS gene demonstrated a sequence change, c.299G>A, in exon 3 that results in an amino acid change, p.Cys100Tyr. This particular amino acid change does not appear to have been described in the literature in other individuals with INS-related disorders. This sequence change has not been described in population databases such as ExAC and gnomAD. The p.Cys100Tyr amino acid change occurs in a region of the INS gene where other missense sequence changes have been described in individuals with INS-related disorders (PMIDs: 22957706, 2295770). A different missense change at the same amino acid residue (p. Cys100Gly) has been reported in a two-year-old individual with diabetes mellitus and was considered likely disease-causing by the authors (PMID: 31216263). Missense INS variants that cause a substitution or creation of a cysteine residue have been identified in multiple families with neonatal diabetes; these cysteine residue changes are predicted to lead to disruption of disulfide bridge formation critical for proinsulin folding (PMID: 18162506). The p.Cys100Tyr change affects a highly conserved amino acid residue located in a domain of the INS protein that is known to be functional. The p.Cys100Tyr substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This collective evidence indicate that this sequence change is the likely pathogenic, however functional studies have not been performed to prove this conclusively -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.