NM_002500.5:c.133A>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002500.5(NEUROD1):​c.133A>C​(p.Thr45Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T45A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: NEUROD1 NM_002500.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.563
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07450989).

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.133A>C	p.Thr45Pro	missense	Exon 2 of 2	NP_002491.3	A0A0S2Z493
	NEUROD1	NR_146175.2		n.88+1702A>C		intron	N/A
	NEUROD1	NR_146176.2		n.88+1702A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEUROD1	ENST00000295108.4	TSL:1 MANE Select	c.133A>C	p.Thr45Pro	missense	Exon 2 of 2	ENSP00000295108.3	Q13562
	NEUROD1	ENST00000683430.1		c.133A>C	p.Thr45Pro	missense	Exon 3 of 3	ENSP00000506907.1	Q13562
	NEUROD1	ENST00000684079.1		c.133A>C	p.Thr45Pro	missense	Exon 3 of 3	ENSP00000507492.1	Q13562

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 73

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.10	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.56
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.28
Sift	Benign	0.22	T
Sift4G	Benign	0.29	T
Polyphen		0.0020	B
Vest4		0.068
MutPred		0.14		Loss of phosphorylation at T45 (P = 0.0457)
MVP		0.92
MPC		0.60
ClinPred		0.067	T
GERP RS		4.4
Varity_R		0.16
gMVP		0.097
Mutation Taster		=91/9	polymorphism

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;