11-2160901-G-T
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM5PP3PP5_Very_Strong
The NM_000207.3(INS):c.71C>A(p.Ala24Asp) 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 Likely risk allele (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A24V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000207.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 35
GnomAD4 exome Cov.: 88
GnomAD4 genome Cov.: 35
ClinVar
Submissions by phenotype
Diabetes mellitus, permanent neonatal 4 Pathogenic:2
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Potent mutations in the INS gene can cause early onset diabetes mellitus which is insulin dependent. May have poor response to sulfonylureas, mutations in this gene can cause beta cell destruction.Sufficient evidence is found to confer the association of this particular variant A24D/rs80356663 with permanent neonatal diabetes. -
not provided Pathogenic:2
DNA sequence analysis of the INS gene demonstrated a sequence change, c.71C>A, in exon 2 that results in an amino acid change, p.Ala24Asp. This sequence change is absent from large population databases such as ExAC and gnomAD (dbSNP rs80356663). The p.Ala24Asp change affects a highly conserved amino acid residue located in region of insulin protein (signal peptide cleavage site) that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala24Asp substitution. This particular amino acid change has been described in multiple patients with permanent neonatal diabetes (PMIDs: 17855560, 18162506, and 18171712). Functional studies have shown that p.Ala24Asp mutant results in aberrant processing of proinsulin to insulin and retention of proinsulin in the endoplasmic reticulum (PMIDs: 19952343, 22357960). Pathogenic variants in INS cause permanent neonatal diabetes [OMIM# 606176]. Most cases of INS-associated neonatal diabetes are inherited in an autosomal dominant manner; however autosomal recessive cases have also been reported. -
This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 24 of the INS protein (p.Ala24Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant neonatal diabetes (PMID: 17855560). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13388). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -
Permanent neonatal diabetes mellitus Other:2
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at