rs1946816

Positions:

• chr4-165419807-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001873.4(CPE):​c.307+40279A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 152,060 control chromosomes in the GnomAD database, including 6,745 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 0.30 (6745 hom., cov: 32)
• Consequence: CPE NM_001873.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00800

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.356 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPE	NM_001873.4	c.307+40279A>C		intron_variant		ENST00000402744.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPE	ENST00000402744.9	c.307+40279A>C		intron_variant		1	NM_001873.4	P1
CPE	ENST00000431967.5	c.-30+4561A>C		intron_variant		4
CPE	ENST00000511992.1	c.-30+1519A>C		intron_variant		5
CPE	ENST00000513982.5	c.-29-44583A>C		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.296 AC: 44950 AN: 151944 Hom.: 6739 Cov.: 32

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.443

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.314

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

GnomAD4 genome AF: 0.296 AC: 44981 AN: 152060 Hom.: 6745 Cov.: 32 AF XY: 0.293 AC XY: 21784 AN XY: 74352

Gnomad4 AFR AF: 0.292

Gnomad4 AMR AF: 0.247

Gnomad4 ASJ AF: 0.368

Gnomad4 EAS AF: 0.370

Gnomad4 SAS AF: 0.296

Gnomad4 FIN AF: 0.265

Gnomad4 NFE AF: 0.302

Gnomad4 OTH AF: 0.314

Alfa AF: 0.301 Hom.: 3156

Bravo AF: 0.295

Asia WGS AF: 0.296 AC: 1032 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	4.6
DANN	Benign	0.39

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

LitVar

Other links and lift over

dbSNP: rs1946816; hg19: chr4-166340959;