2-181680491-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0170

Publications

8 publications found

Variant links:

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]

NEUROD1 links:

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

CERKL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NEUROD1	NM_002500.5 link	c.-73G>A	5_prime_UTR_variant	Exon 1 of 2	ENST00000295108.4	NP_002491.3	Q13562A0A0S2Z493
NEUROD1	NR_146175.2 link	n.27G>A	non_coding_transcript_exon_variant	Exon 1 of 2
NEUROD1	NR_146176.2 link	n.27G>A	non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEUROD1	ENST00000295108.4 link	c.-73G>A		5_prime_UTR_variant	Exon 1 of 2	1	NM_002500.5	ENSP00000295108.3		Q13562

Frequencies

GnomAD3 genomes

AF:

0.690

AC:

104905

AN:

152108

Hom.:

36689

Cov.:

show subpopulations

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:

AN:

Hom.:

Cov.:

AF XY:

0.676

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.833

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.750

AC:

AN:

East Asian (EAS)

AF:

1.00

AC:

AN:

South Asian (SAS)

AF:

0.750

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.653

AC:

AN:

Other (OTH)

AF:

0.667

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.543

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.690

AC:

104995

AN:

152226

Hom.:

36727

Cov.:

AF XY:

0.697

AC XY:

51845

AN XY:

74428

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1682

3364

5047

6729

8411

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.646

Hom.:

108776

Bravo

AF:

0.694

Asia WGS

AF:

0.837

AC:

2913

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Maturity-onset diabetes of the young type 6

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

8.8

(source)

DANN

Benign

0.96

PhyloP100

-0.017

PromoterAI

0.034

Neutral

(source)

Mutation Taster

=297/3

polymorphism (auto)

(source)

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

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2-181680491-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over