chr2-181677112-AT-A

Variant names:

• chr2-181677112-AT-A
• rs374172497
• NM_002500.5:c.*677delA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_002500.5(NEUROD1):​c.*677delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.075 (33 hom., cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEUROD1 NM_002500.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.959
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 33 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEUROD1	NM_002500.5	c.*677delA		3_prime_UTR_variant	Exon 2 of 2	ENST00000295108.4	NP_002491.3
NEUROD1	NR_146175.2	n.88+3317delA		intron_variant	Intron 1 of 1
NEUROD1	NR_146176.2	n.88+3317delA		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEUROD1	ENST00000295108.4	c.*677delA		3_prime_UTR_variant	Exon 2 of 2	1	NM_002500.5	ENSP00000295108.3

Frequencies

GnomAD3 genomes AF: 0.0750 AC: 3606 AN: 48106 Hom.: 33 Cov.: 0

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.0672

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.0883

Gnomad EAS AF: 0.0875

Gnomad SAS AF: 0.0765

Gnomad FIN AF: 0.0335

Gnomad MID AF: 0.0938

Gnomad NFE AF: 0.0925

Gnomad OTH AF: 0.0927

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 80 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 50

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 78

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.0749 AC: 3606 AN: 48126 Hom.: 33 Cov.: 0 AF XY: 0.0715 AC XY: 1507 AN XY: 21084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0321 AC: 439 AN: 13674

American (AMR) AF: 0.111 AC: 310 AN: 2786

Ashkenazi Jewish (ASJ) AF: 0.0883 AC: 130 AN: 1472

East Asian (EAS) AF: 0.0877 AC: 146 AN: 1664

South Asian (SAS) AF: 0.0767 AC: 92 AN: 1200

European-Finnish (FIN) AF: 0.0335 AC: 16 AN: 478

Middle Eastern (MID) AF: 0.0882 AC: 3 AN: 34

European-Non Finnish (NFE) AF: 0.0925 AC: 2392 AN: 25872

Other (OTH) AF: 0.0923 AC: 53 AN: 574

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.96
Mutation Taster		=100/0	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: rs374172497; hg19: chr2-182541839;