rs1946816

Variant names:

• chr4-165419807-A-C
• rs1946816
• NM_001873.4:c.307+40279A>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+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
• Publications: 7 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=-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 rank	MANE	Protein	UniProt
CPE	NM_001873.4	c.307+40279A>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+40279A>C		intron_variant	Intron 1 of 8	1	NM_001873.4	ENSP00000386104.4
CPE	ENST00000511992.1	c.-30+1519A>C		intron_variant	Intron 1 of 4	5		ENSP00000423699.1
CPE	ENST00000431967.5	c.-30+4561A>C		intron_variant	Intron 1 of 3	4		ENSP00000416601.1
CPE	ENST00000513982.5	c.-29-44583A>C		intron_variant	Intron 1 of 3	4		ENSP00000424830.1

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

African (AFR) AF: 0.292 AC: 12098 AN: 41468

American (AMR) AF: 0.247 AC: 3766 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1276 AN: 3470

East Asian (EAS) AF: 0.370 AC: 1911 AN: 5164

South Asian (SAS) AF: 0.296 AC: 1426 AN: 4820

European-Finnish (FIN) AF: 0.265 AC: 2799 AN: 10582

Middle Eastern (MID) AF: 0.390 AC: 114 AN: 292

European-Non Finnish (NFE) AF: 0.302 AC: 20525 AN: 67968

Other (OTH) AF: 0.314 AC: 662 AN: 2110

Alfa AF: 0.303 Hom.: 3584

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
PhyloP100		-0.0080
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: rs1946816; hg19: chr4-166340959;