2-181678111-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002500.5(NEUROD1):c.750C>A(p.Ser250Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000273 in 1,614,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

NEUROD1
NM_002500.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: -0.302

Publications

5 publications found

Variant links:

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]

NEUROD1 links:

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

CERKL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06332633).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002500.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEUROD1	NM_002500.5	MANE Select	c.750C>A	p.Ser250Arg	missense	Exon 2 of 2	NP_002491.3
NEUROD1	NR_146175.2		n.88+2319C>A		intron	N/A
NEUROD1	NR_146176.2		n.88+2319C>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEUROD1	ENST00000295108.4	TSL:1 MANE Select	c.750C>A	p.Ser250Arg	missense	Exon 2 of 2	ENSP00000295108.3
NEUROD1	ENST00000683430.1		c.750C>A	p.Ser250Arg	missense	Exon 3 of 3	ENSP00000506907.1
NEUROD1	ENST00000684079.1		c.750C>A	p.Ser250Arg	missense	Exon 3 of 3	ENSP00000507492.1

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000155

AC:

AN:

251464

AF XY:

0.000199

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000277

AC:

405

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000261

AC XY:

190

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000331

AC:

368

AN:

1112010

Other (OTH)

AF:

0.000116

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

114

142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000230

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41578

American (AMR)

AF:

0.00

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000622

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000294

Hom.:

Bravo

AF:

0.000181

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000115

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Nov 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 250 of the NEUROD1 protein (p.Ser250Arg). This variant is present in population databases (rs201293992, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal dominant maturity onset diabetes of the young (PMID: 30259503). ClinVar contains an entry for this variant (Variation ID: 549508). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt NEUROD1 protein function with a negative predictive value of 80%. 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.

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Uncertain:1

May 20, 2025

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.750C>A (p.Ser250Arg) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00016 in 251464 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NEUROD1 causing Permanent Neonatal Diabetes And Neurological Abnormalities, allowing no conclusion about variant significance. c.750C>A has been observed in individual(s) suspected with Monogenic Diabetes (Komazec_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Permanent Neonatal Diabetes And Neurological Abnormalities. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30259503). ClinVar contains an entry for this variant (Variation ID: 549508). Based on the evidence outlined above, the variant was classified as uncertain significance.

Maturity-onset diabetes of the young type 6

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Monogenic diabetes

Uncertain:1

Jul 14, 2017

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

ACMG Criteria:BP4 (9 predictors)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.25

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.69

M_CAP

Benign

0.018

MetaRNN

Benign

0.063

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.69

PhyloP100

-0.30

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.0

REVEL

Benign

0.17

Sift

Benign

0.15

Sift4G

Benign

0.17

Polyphen

0.68

Vest4

0.21

MutPred

0.28

Loss of glycosylation at S250 (P = 0.0191)

MVP

0.73

MPC

1.2

ClinPred

0.13

GERP RS

2.0

Varity_R

0.28

gMVP

0.35

Mutation Taster

=77/23

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over