NM_001873.4:c.307+33711T>C

Variant names:

• chr4-165413239-T-C
• rs10517844
• NM_001873.4:c.307+33711T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001873.4(CPE):​c.307+33711T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 152,090 control chromosomes in the GnomAD database, including 6,422 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.29 (6422 hom., cov: 32)
• Consequence: CPE NM_001873.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.727
• Publications: 6 publications found

Genes affected

CPE (HGNC:2303): (carboxypeptidase E) This gene encodes a member of the M14 family of metallocarboxypeptidases. The encoded preproprotein is proteolytically processed to generate the mature peptidase. This peripheral membrane protein cleaves C-terminal amino acid residues and is involved in the biosynthesis of peptide hormones and neurotransmitters, including insulin. This protein may also function independently of its peptidase activity, as a neurotrophic factor that promotes neuronal survival, and as a sorting receptor that binds to regulated secretory pathway proteins, including prohormones. Mutations in this gene are implicated in type 2 diabetes. [provided by RefSeq, Nov 2015]

CPE Gene-Disease associations (from GenCC):

• BDV syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPE	NM_001873.4	c.307+33711T>C		intron_variant	Intron 1 of 8	ENST00000402744.9	NP_001864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPE	ENST00000402744.9	c.307+33711T>C		intron_variant	Intron 1 of 8	1	NM_001873.4	ENSP00000386104.4
CPE	ENST00000513982.5	c.-29-51151T>C		intron_variant	Intron 1 of 3	4		ENSP00000424830.1

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43608 AN: 151972 Hom.: 6412 Cov.: 32

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.307

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

GnomAD4 genome AF: 0.287 AC: 43649 AN: 152090 Hom.: 6422 Cov.: 32 AF XY: 0.284 AC XY: 21120 AN XY: 74316

African (AFR) AF: 0.245 AC: 10154 AN: 41482

American (AMR) AF: 0.245 AC: 3740 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1340 AN: 3470

East Asian (EAS) AF: 0.311 AC: 1600 AN: 5152

South Asian (SAS) AF: 0.307 AC: 1478 AN: 4812

European-Finnish (FIN) AF: 0.258 AC: 2728 AN: 10576

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.317 AC: 21522 AN: 67994

Other (OTH) AF: 0.307 AC: 650 AN: 2114

Alfa AF: 0.309 Hom.: 5418

Bravo AF: 0.283

Asia WGS AF: 0.274 AC: 954 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.7
DANN	Benign	0.65
PhyloP100		-0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10517844; hg19: chr4-166334391;