2-181678728-T-C

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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:4
• Conservation: PhyloP100: 0.563

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 -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 id is 801839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-181678728-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
NEUROD1	NM_002500.5	c.133A>G	p.Thr45Ala	missense_variant	2/2	ENST00000295108.4
NEUROD1	NR_146175.2	n.88+1702A>G		intron_variant, non_coding_transcript_variant
NEUROD1	NR_146176.2	n.88+1702A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEUROD1	ENST00000295108.4	c.133A>G	p.Thr45Ala	missense_variant	2/2	1	NM_002500.5	P1

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

GnomAD3 exomes AF: 0.702 AC: 173739 AN: 247414 Hom.: 62114 AF XY: 0.703 AC XY: 94054 AN XY: 133770

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 SAS exome AF: 0.850

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

Gnomad4 AFR exome AF: 0.738

Gnomad4 AMR exome AF: 0.759

Gnomad4 ASJ exome AF: 0.645

Gnomad4 EAS exome AF: 0.919

Gnomad4 SAS exome AF: 0.848

Gnomad4 FIN exome AF: 0.642

Gnomad4 NFE exome AF: 0.628

Gnomad4 OTH exome AF: 0.676

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

Gnomad4 AFR AF: 0.738

Gnomad4 AMR AF: 0.714

Gnomad4 ASJ AF: 0.661

Gnomad4 EAS AF: 0.917

Gnomad4 SAS AF: 0.843

Gnomad4 FIN AF: 0.657

Gnomad4 NFE AF: 0.628

Gnomad4 OTH AF: 0.670

Alfa AF: 0.644 Hom.: 78692

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Maturity onset diabetes mellitus in young Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

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
MutationTaster	Benign	1.0	P
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

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