2-181680491-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002500.5(NEUROD1):c.-73G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.69 in 152,322 control chromosomes in the GnomAD database, including 36,747 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.69 (36727 hom., cov: 34)
  • Exomes 𝑓: 0.68 (20 hom.)
• Consequence: NEUROD1 NM_002500.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0170

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 2-181680491-C-T is Benign according to our data. Variant chr2-181680491-C-T is described in ClinVar as [Benign]. Clinvar id is 333042.Status of the report is criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
NEUROD1	NM_002500.5	c.-73G>A		5_prime_UTR_variant	1/2	ENST00000295108.4
NEUROD1	NR_146175.2	n.27G>A		non_coding_transcript_exon_variant	1/2
NEUROD1	NR_146176.2	n.27G>A		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEUROD1	ENST00000295108.4	c.-73G>A		5_prime_UTR_variant	1/2	1	NM_002500.5	P1

Frequencies

GnomAD3 genomes AF: 0.690 AC: 104905 AN: 152108 Hom.: 36689 Cov.: 34

Gnomad AFR AF: 0.759

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.715

Gnomad ASJ AF: 0.661

Gnomad EAS AF: 0.917

Gnomad SAS AF: 0.841

Gnomad FIN AF: 0.656

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.676

GnomAD4 exome AF: 0.677 AC: 65 AN: 96 Hom.: 20 Cov.: 0 AF XY: 0.676 AC XY: 50 AN XY: 74

Gnomad4 AFR exome AF: 0.833

Gnomad4 ASJ exome AF: 0.750

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.750

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.653

Gnomad4 OTH exome AF: 0.667

GnomAD4 genome AF: 0.690 AC: 104995 AN: 152226 Hom.: 36727 Cov.: 34 AF XY: 0.697 AC XY: 51845 AN XY: 74428

Gnomad4 AFR AF: 0.759

Gnomad4 AMR AF: 0.716

Gnomad4 ASJ AF: 0.661

Gnomad4 EAS AF: 0.917

Gnomad4 SAS AF: 0.841

Gnomad4 FIN AF: 0.656

Gnomad4 NFE AF: 0.626

Gnomad4 OTH AF: 0.672

Alfa AF: 0.638 Hom.: 44860

Bravo AF: 0.694

Asia WGS AF: 0.837 AC: 2913 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	8.8
Dann	Benign	0.96

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: rs2583016; hg19: chr2-182545218;