2-181678244-TGGG-TGGGG

Variant names:

• chr2-181678244-T-TG
• rs387906384
• NM_002500.5:c.616dupC

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

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:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: NEUROD1 NM_002500.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 2.14
• Publications: 6 publications found

Genes affected

NEUROD1 (HGNC:7762): (neuronal differentiation 1) This gene encodes a member of the NeuroD family of basic helix-loop-helix (bHLH) transcription factors. The protein forms heterodimers with other bHLH proteins and activates transcription of genes that contain a specific DNA sequence known as the E-box. It regulates expression of the insulin gene, and mutations in this gene result in type II diabetes mellitus. [provided by RefSeq, Jul 2008]

CERKL (HGNC:21699): (ceramide kinase like) This gene was initially identified as a locus (RP26) associated with an autosomal recessive form of retinitis pigmentosa (arRP) disease. This gene encodes a protein with ceramide kinase-like domains, however, the protein does not phosphorylate ceramide and its target substrate is currently unknown. This protein may be a negative regulator of apoptosis in photoreceptor cells. Mutations in this gene cause a form of retinitis pigmentosa characterized by autosomal recessive cone and rod dystrophy (arCRD). Alternative splicing of this gene results in multiple transcript variants encoding different isoforms and non-coding transcripts.[provided by RefSeq, May 2010]

CERKL Gene-Disease associations (from GenCC):

• CERKL-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 26

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP5: Variant 2-181678244-T-TG is Pathogenic according to our data. Variant chr2-181678244-T-TG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 7854.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

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

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEUROD1	ENST00000295108.4	c.616dupC	p.His206ProfsTer38	frameshift_variant	Exon 2 of 2	1	NM_002500.5	ENSP00000295108.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000240 AC: 6 AN: 250042 AF XY: 0.0000369

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461518 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14 AN XY: 727068

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.0000377 AC: 2 AN: 53082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 31

Alfa AF: 0.000130 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Feb 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 14, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Maturity-onset diabetes of the young type 6 Pathogenic:1

Nov 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

NEUROD1-related disorder Pathogenic:1

Jan 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Apr 22, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs387906384; hg19: chr2-182542971; COSMIC: COSV54548339; COSMIC: COSV54548339;