2-181680491-C-T

Variant names:

• chr2-181680491-C-T
• rs2583016
• NM_002500.5:c.-73G>A

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.-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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0170
• Publications: 8 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: G2P, Labcorp Genetics (formerly Invitae)
• 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 (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 VariationId is 333042.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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002500.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEUROD1	NM_002500.5	MANE Select	c.-73G>A		5_prime_UTR	Exon 1 of 2	NP_002491.3	A0A0S2Z493
	NEUROD1	NR_146175.2		n.27G>A		non_coding_transcript_exon	Exon 1 of 2
	NEUROD1	NR_146176.2		n.27G>A		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEUROD1	ENST00000295108.4	TSL:1 MANE Select	c.-73G>A		5_prime_UTR	Exon 1 of 2	ENSP00000295108.3	Q13562
	NEUROD1	ENST00000683430.1		c.-188G>A		5_prime_UTR	Exon 1 of 3	ENSP00000506907.1	Q13562
	NEUROD1	ENST00000684079.1		c.-225G>A		5_prime_UTR	Exon 1 of 3	ENSP00000507492.1	Q13562

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

African (AFR) AF: 0.833 AC: 5 AN: 6

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 3 AN: 4

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AF: 0.750 AC: 3 AN: 4

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.653 AC: 47 AN: 72

Other (OTH) AF: 0.667 AC: 4 AN: 6

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

African (AFR) AF: 0.759 AC: 31517 AN: 41528

American (AMR) AF: 0.716 AC: 10953 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 2295 AN: 3470

East Asian (EAS) AF: 0.917 AC: 4762 AN: 5192

South Asian (SAS) AF: 0.841 AC: 4059 AN: 4826

European-Finnish (FIN) AF: 0.656 AC: 6951 AN: 10590

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.626 AC: 42554 AN: 68004

Other (OTH) AF: 0.672 AC: 1419 AN: 2112

Alfa AF: 0.646 Hom.: 108776

Bravo AF: 0.694

Asia WGS AF: 0.837 AC: 2913 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Maturity-onset diabetes of the young type 6 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.8
DANN	Benign	0.96
PhyloP100		-0.017
PromoterAI		0.034	Neutral
Mutation Taster		=297/3	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: rs2583016; hg19: chr2-182545218;