2-181678271-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002500.5(NEUROD1):c.590C>A(p.Pro197His) variant causes a missense change. The variant allele was found at a frequency of 0.0218 in 1,614,140 control chromosomes in the GnomAD database, including 445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.016 ( 29 hom., cov: 32)

Exomes 𝑓: 0.022 ( 416 hom. )

Consequence

NEUROD1
NM_002500.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 5.76

Publications

27 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005200088).

BP6

Variant 2-181678271-G-T is Benign according to our data. Variant chr2-181678271-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129763.We mark this variant Benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.016 (2432/152310) while in subpopulation NFE AF = 0.025 (1701/68024). AF 95% confidence interval is 0.024. There are 29 homozygotes in GnomAd4. There are 1093 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 29 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEUROD1	NM_002500.5 link	c.590C>A	p.Pro197His	missense_variant	Exon 2 of 2	ENST00000295108.4	NP_002491.3	Q13562A0A0S2Z493
NEUROD1	NR_146175.2 link	n.88+2159C>A		intron_variant	Intron 1 of 1
NEUROD1	NR_146176.2 link	n.88+2159C>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEUROD1	ENST00000295108.4 link	c.590C>A	p.Pro197His	missense_variant	Exon 2 of 2	1	NM_002500.5	ENSP00000295108.3		Q13562

Frequencies

GnomAD3 genomes

AF:

0.0160

AC:

2434

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00393

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0128

Gnomad ASJ

AF:

0.0533

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0195

Gnomad FIN

AF:

0.00311

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0250

Gnomad OTH

AF:

0.0229

GnomAD2 exomes

AF:

0.0193

AC:

4852

AN:

251302

AF XY:

0.0204

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.0185

Gnomad ASJ exome

AF:

0.0481

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00375

Gnomad NFE exome

AF:

0.0243

Gnomad OTH exome

AF:

0.0257

GnomAD4 exome

AF:

0.0224

AC:

32811

AN:

1461830

Hom.:

416

Cov.:

AF XY:

0.0227

AC XY:

16507

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.00281

AC:

AN:

33480

American (AMR)

AF:

0.0182

AC:

815

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0467

AC:

1220

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0215

AC:

1855

AN:

86258

European-Finnish (FIN)

AF:

0.00345

AC:

184

AN:

53364

Middle Eastern (MID)

AF:

0.0394

AC:

227

AN:

5766

European-Non Finnish (NFE)

AF:

0.0243

AC:

26989

AN:

1112006

Other (OTH)

AF:

0.0235

AC:

1421

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

2178

4356

6534

8712

10890

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

972

1944

2916

3888

4860

<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:

0.0160

AC:

2432

AN:

152310

Hom.:

Cov.:

AF XY:

0.0147

AC XY:

1093

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00392

AC:

163

AN:

41576

American (AMR)

AF:

0.0128

AC:

196

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0533

AC:

185

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.0193

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00311

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0250

AC:

1701

AN:

68024

Other (OTH)

AF:

0.0227

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

121

242

363

484

605

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0226

Hom.:

159

Bravo

AF:

0.0162

TwinsUK

AF:

0.0245

AC:

ALSPAC

AF:

0.0228

AC:

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0270

AC:

232

ExAC

AF:

0.0189

AC:

2296

Asia WGS

AF:

0.00895

AC:

AN:

3478

EpiCase

AF:

0.0309

EpiControl

AF:

0.0319

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30259503, 31578821) -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypoinsulinemia

Uncertain:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

The role of NEUROD1 gene is known to be associated with neonatal onset diabetes due to pancreatic aplasia, leading to insulin dependence. It is associated with extra pancreatic manifestation of neurological impairment. However, no sufficient evidence is found to ascertain the role of rs8192556 variant in Diabetes Mellitus yet. -

Maturity-onset diabetes of the young type 6

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Monogenic diabetes

Benign:1

Jan 25, 2019

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

ACMG criteria: BA1 (1.9% overall MAF in gnomAD), BS2 (429 cases and 438 Controls in T2DM)= benign; REVEL 0.211 +BP4/4 predictors + PP3/6 predictors= conflicting evidence, not using -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.43

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Benign

0.21

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0052

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.9

PhyloP100

5.8

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.21

Sift

Benign

0.034

Sift4G

Benign

0.33

Polyphen

0.47

Vest4

0.18

MPC

1.4

ClinPred

0.023

GERP RS

6.0

Varity_R

0.44

gMVP

0.65

Mutation Taster

=79/21

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over