rs6855889

Variant names:

• chr4-165383502-C-T
• rs6855889
• NM_001873.4:c.307+3974C>T

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+3974C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 152,044 control chromosomes in the GnomAD database, including 6,375 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 0.27 (6375 hom., cov: 33)
• Consequence: CPE NM_001873.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.263
• 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=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001873.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPE	NM_001873.4	MANE Select	c.307+3974C>T		intron	N/A	NP_001864.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPE	ENST00000402744.9	TSL:1 MANE Select	c.307+3974C>T		intron	N/A	ENSP00000386104.4
	CPE	ENST00000513982.5	TSL:4	c.-30+22191C>T		intron	N/A	ENSP00000424830.1

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40737 AN: 151928 Hom.: 6355 Cov.: 33

Gnomad AFR AF: 0.440

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.150

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.242

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

GnomAD4 genome AF: 0.268 AC: 40807 AN: 152044 Hom.: 6375 Cov.: 33 AF XY: 0.265 AC XY: 19692 AN XY: 74346

African (AFR) AF: 0.440 AC: 18248 AN: 41426

American (AMR) AF: 0.189 AC: 2893 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 632 AN: 3472

East Asian (EAS) AF: 0.212 AC: 1095 AN: 5162

South Asian (SAS) AF: 0.257 AC: 1239 AN: 4822

European-Finnish (FIN) AF: 0.222 AC: 2344 AN: 10564

Middle Eastern (MID) AF: 0.147 AC: 43 AN: 292

European-Non Finnish (NFE) AF: 0.201 AC: 13642 AN: 67994

Other (OTH) AF: 0.239 AC: 505 AN: 2112

Alfa AF: 0.235 Hom.: 857

Bravo AF: 0.272

Asia WGS AF: 0.254 AC: 882 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.8
DANN	Benign	0.82
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

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: rs6855889; hg19: chr4-166304654;