rs8192556

chr2-181678271-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 5.76

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]

ACMG classification

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 GnomAd at 2434 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2434 AN: 152192 Hom.: 29 Cov.: 32

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.: 76 AF XY: 0.0204 AC XY: 2773 AN XY: 135820

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.: 30 AF XY: 0.0227 AC XY: 16507 AN XY: 727204

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.: 29 Cov.: 32 AF XY: 0.0147 AC XY: 1093 AN XY: 74480

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.: 86

Bravo AF: 0.0162

TwinsUK AF: 0.0245 AC: 91

ALSPAC AF: 0.0228 AC: 88

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0270 AC: 232

ExAC AF: 0.0189 AC: 2296

Asia WGS AF: 0.00895 AC: 34 AN: 3478

EpiCase AF: 0.0309

EpiControl AF: 0.0319

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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	- -

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	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.21
Sift	Benign	0.034	D
Sift4G	Benign	0.33	T
Polyphen		0.47	P
Vest4		0.18
MPC		1.4
ClinPred		0.023	T
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

Other links and lift over

dbSNP: rs8192556; hg19: chr2-182542998;