2-181678244-TGGG-TGGGG
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5BS2
The NM_002500.5(NEUROD1):c.616dupC(p.His206ProfsTer38) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,518 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002500.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NEUROD1 | NM_002500.5 | c.616dupC | p.His206ProfsTer38 | frameshift_variant | Exon 2 of 2 | ENST00000295108.4 | NP_002491.3 | |
NEUROD1 | NR_146175.2 | n.88+2185dupC | intron_variant | Intron 1 of 1 | ||||
NEUROD1 | NR_146176.2 | n.88+2185dupC | intron_variant | Intron 1 of 1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461518Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14AN XY: 727068
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Published functional studies demonstrate a damaging effect as the variant abolishes ability to bind co-activators and is unable to activate target genes (Malecki et al., 1999); Frameshift variant predicted to result in protein truncation, as the last 151 amino acids are replaced with 37 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 28664602, 36208030, 10545951, 34556497) -
The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.His206Profs*38) in the NEUROD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 151 amino acid(s) of the NEUROD1 protein. This premature translational stop signal has been observed in individual(s) with autosomal dominant maturity onset diabetes of the young (PMID: 10545951, 28664602). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7854). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects NEUROD1 function (PMID: 10545951). For these reasons, this variant has been classified as Pathogenic. -
Maturity-onset diabetes of the young type 6 Pathogenic:1
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NEUROD1-related disorder Pathogenic:1
The NEUROD1 c.616dupC variant is predicted to result in a frameshift and premature protein termination (p.His206Profs*38). This variant has been reported in multiple individuals from two families affected with MODY and segregated with disease in these families (Malecki et al 1999. PubMed ID: 10545951; Horikawa et al. 2017. PubMed ID: 28664602). This variant is reported in 0.0100% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Frameshift variants in NEUROD1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -
not specified Uncertain:1
Variant summary: NEUROD1 c.616dupC (p.His206ProfsX38) located in the last exon (exon 2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have not been observed at our laboratory but have been reported in association with Monogenic Diabetes in the HGMD database. The variant allele was found at a frequency of 2.4e-05 in 250042 control chromosomes, indicated to have failed random forest filtering and listed as being multialleleic with 2-182542971-TGGG-T (p.Pro205del) in the gnomAD exomes database, suggesting technically problematic issues with its occurrence. c.616dupC has been reported in the literature to segregate with disease in families with multiple individuals affected with Monogenic Diabetes and in settings of multigene panel testing for Monogenic Diabetes (example, Malecki_1999, Horikawa_2018, Saint-Martin_2022). These data indicate that the variant is very likely to be associated with disease in a presumably dominant mode of inheritance. At least one publication reports experimental evidence evaluating an impact on protein function (Malecki_1999). The most pronounced variant effect results in impaired NEUROD1 transactivation activity presumably due to disruption of the C-terminal transactivation domain. The ClinGen expert panel states this gene as having "limited" validity for association to a phenotype of autosomal dominant monogenic diabetes and "moderate" validity for association to a phenotype of autosomal recessive monogenic diabetes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at