ENST00000684145.1:c.-455+4235G>A

Variant names:

• chr2-181676195-C-T
• rs187310461
• ENST00000684145.1:c.-455+4235G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000684145.1(CERKL):​c.-455+4235G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 152,166 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.0023 (3 hom., cov: 33)
• Consequence: CERKL ENST00000684145.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.363
• Publications: 1 publications found

Genes affected

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]

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 Gene-Disease associations (from GenCC):

• maturity-onset diabetes of the young type 6

  Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• monogenic diabetes

  Inheritance: AD, AR Classification: MODERATE, LIMITED Submitted by: ClinGen
• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-181676195-C-T is Benign according to our data. Variant chr2-181676195-C-T is described in ClinVar as Benign. ClinVar VariationId is 333018.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000684145.1. 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	NR_146175.2		n.89-2648G>A		intron	N/A
	NEUROD1	NR_146176.2		n.88+4235G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CERKL	ENST00000684145.1		c.-455+4235G>A		intron	N/A	ENSP00000508396.1	G0XYE7
	CERKL	ENST00000479558.5	TSL:2	c.-378+4235G>A		intron	N/A	ENSP00000507265.1	A0A804HIX5
	NEUROD1	ENST00000496876.2	TSL:4	n.399-2648G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00234 AC: 356 AN: 152048 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00380

Gnomad OTH AF: 0.000958

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00234 AC: 356 AN: 152166 Hom.: 3 Cov.: 33 AF XY: 0.00214 AC XY: 159 AN XY: 74406

African (AFR) AF: 0.000771 AC: 32 AN: 41528

American (AMR) AF: 0.000785 AC: 12 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00396 AC: 42 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00380 AC: 258 AN: 67960

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00254 Hom.: 0

Bravo AF: 0.00218

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Maturity-onset diabetes of the young type 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.22
DANN	Benign	0.28
PhyloP100		-0.36

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs187310461; hg19: chr2-182540922;