rs8192556

Positions:

chr2-181678271-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000295108.4(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
ENST00000295108.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.76

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 Likely_benign, oryginal submissions are: {Benign=7, Uncertain_significance=1}. Variant chr2-181678271-G-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2432 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NEUROD1	NM_002500.5 linkuse as main transcript	c.590C>A	p.Pro197His	missense_variant	2/2	ENST00000295108.4	NP_002491.3
NEUROD1	NR_146175.2 linkuse as main transcript	n.88+2159C>A		intron_variant, non_coding_transcript_variant
NEUROD1	NR_146176.2 linkuse as main transcript	n.88+2159C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEUROD1	ENST00000295108.4 linkuse as main transcript	c.590C>A	p.Pro197His	missense_variant	2/2	1	NM_002500.5	ENSP00000295108	P1

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

GnomAD3 exomes

AF:

0.0193

AC:

4852

AN:

251302

Hom.:

AF XY:

0.0204

AC XY:

2773

AN XY:

135820

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 SAS exome

AF:

0.0219

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

Gnomad4 AFR exome

AF:

0.00281

Gnomad4 AMR exome

AF:

0.0182

Gnomad4 ASJ exome

AF:

0.0467

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0215

Gnomad4 FIN exome

AF:

0.00345

Gnomad4 NFE exome

AF:

0.0243

Gnomad4 OTH exome

AF:

0.0235

GnomAD4 genome

AF:

0.0160

AC:

2432

AN:

152310

Hom.:

Cov.:

AF XY:

0.0147

AC XY:

1093

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00392

Gnomad4 AMR

AF:

0.0128

Gnomad4 ASJ

AF:

0.0533

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0193

Gnomad4 FIN

AF:

0.00311

Gnomad4 NFE

AF:

0.0250

Gnomad4 OTH

AF:

0.0227

Alfa

AF:

0.0244

Hom.:

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2019	This variant is associated with the following publications: (PMID: 30259503, 31578821) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hypoinsulinemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jan 25, 2019

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

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

MutationTaster

Benign

1.0

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over