2-181678728-T-C

Variant names:

• chr2-181678728-T-C
• rs1801262
• NM_002500.5:c.133A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002500.5(NEUROD1):​c.133A>G​(p.Thr45Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.661 in 1,611,182 control chromosomes in the GnomAD database, including 356,278 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (36062 hom., cov: 30)
  • Exomes 𝑓: 0.66 (320216 hom.)
• Consequence: NEUROD1 NM_002500.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.563
• Publications: 90 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.798682E-7).
• BP6: Variant 2-181678728-T-C is Benign according to our data. Variant chr2-181678728-T-C is described in ClinVar as Benign. ClinVar VariationId is 801839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.895 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEUROD1	NM_002500.5	c.133A>G	p.Thr45Ala	missense_variant	Exon 2 of 2	ENST00000295108.4	NP_002491.3
NEUROD1	NR_146175.2	n.88+1702A>G		intron_variant	Intron 1 of 1
NEUROD1	NR_146176.2	n.88+1702A>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEUROD1	ENST00000295108.4	c.133A>G	p.Thr45Ala	missense_variant	Exon 2 of 2	1	NM_002500.5	ENSP00000295108.3

Frequencies

GnomAD3 genomes AF: 0.685 AC: 103930 AN: 151820 Hom.: 36024 Cov.: 30

Gnomad AFR AF: 0.738

Gnomad AMI AF: 0.341

Gnomad AMR AF: 0.714

Gnomad ASJ AF: 0.661

Gnomad EAS AF: 0.916

Gnomad SAS AF: 0.843

Gnomad FIN AF: 0.657

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.674

GnomAD2 exomes AF: 0.702 AC: 173739 AN: 247414 AF XY: 0.703

Gnomad AFR exome AF: 0.738

Gnomad AMR exome AF: 0.761

Gnomad ASJ exome AF: 0.639

Gnomad EAS exome AF: 0.916

Gnomad FIN exome AF: 0.640

Gnomad NFE exome AF: 0.623

Gnomad OTH exome AF: 0.675

GnomAD4 exome AF: 0.658 AC: 960681 AN: 1459244 Hom.: 320216 Cov.: 73 AF XY: 0.663 AC XY: 481242 AN XY: 725666

African (AFR) AF: 0.738 AC: 24627 AN: 33358

American (AMR) AF: 0.759 AC: 33671 AN: 44338

Ashkenazi Jewish (ASJ) AF: 0.645 AC: 16838 AN: 26096

East Asian (EAS) AF: 0.919 AC: 36468 AN: 39678

South Asian (SAS) AF: 0.848 AC: 73012 AN: 86066

European-Finnish (FIN) AF: 0.642 AC: 34261 AN: 53330

Middle Eastern (MID) AF: 0.655 AC: 3772 AN: 5760

European-Non Finnish (NFE) AF: 0.628 AC: 697274 AN: 1110312

Other (OTH) AF: 0.676 AC: 40758 AN: 60306

GnomAD4 genome AF: 0.685 AC: 104019 AN: 151938 Hom.: 36062 Cov.: 30 AF XY: 0.692 AC XY: 51363 AN XY: 74248

African (AFR) AF: 0.738 AC: 30573 AN: 41422

American (AMR) AF: 0.714 AC: 10915 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 2296 AN: 3472

East Asian (EAS) AF: 0.917 AC: 4704 AN: 5130

South Asian (SAS) AF: 0.843 AC: 4050 AN: 4804

European-Finnish (FIN) AF: 0.657 AC: 6939 AN: 10560

Middle Eastern (MID) AF: 0.592 AC: 173 AN: 292

European-Non Finnish (NFE) AF: 0.628 AC: 42647 AN: 67958

Other (OTH) AF: 0.670 AC: 1412 AN: 2108

Alfa AF: 0.648 Hom.: 145221

Bravo AF: 0.688

TwinsUK AF: 0.627 AC: 2326

ALSPAC AF: 0.624 AC: 2403

ESP6500AA AF: 0.743 AC: 3275

ESP6500EA AF: 0.632 AC: 5431

ExAC AF: 0.696 AC: 84490

Asia WGS AF: 0.839 AC: 2917 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maturity onset diabetes mellitus in young Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	11
DANN	Benign	0.66
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.000040	N
LIST_S2	Benign	0.073	T
MetaRNN	Benign	5.8e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.56
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.0070
MPC		0.45
ClinPred		0.00014	T
GERP RS		4.4
Varity_R		0.062
gMVP		0.069
Mutation Taster		=98/2	polymorphism (auto)

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: rs1801262; hg19: chr2-182543455; COSMIC: COSV54550381; COSMIC: COSV54550381;