chr4-165438269-T-C

Variant names:

• chr4-165438269-T-C
• rs4481204
• NM_001873.4:c.308-26121T>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.308-26121T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 151,876 control chromosomes in the GnomAD database, including 8,126 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 0.32 (8126 hom., cov: 31)
• Consequence: CPE NM_001873.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPE	NM_001873.4	c.308-26121T>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.308-26121T>C		intron_variant	Intron 1 of 8	1	NM_001873.4	ENSP00000386104.4
CPE	ENST00000511992.1	c.-30+19981T>C		intron_variant	Intron 1 of 4	5		ENSP00000423699.1
CPE	ENST00000431967.5	c.-30+23023T>C		intron_variant	Intron 1 of 3	4		ENSP00000416601.1
CPE	ENST00000513982.5	c.-29-26121T>C		intron_variant	Intron 1 of 3	4		ENSP00000424830.1

Frequencies

GnomAD3 genomes AF: 0.322 AC: 48855 AN: 151758 Hom.: 8120 Cov.: 31

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.551

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.336

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.346

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

GnomAD4 genome AF: 0.322 AC: 48880 AN: 151876 Hom.: 8126 Cov.: 31 AF XY: 0.320 AC XY: 23731 AN XY: 74202

African (AFR) AF: 0.252 AC: 10464 AN: 41444

American (AMR) AF: 0.284 AC: 4321 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.336 AC: 1165 AN: 3470

East Asian (EAS) AF: 0.371 AC: 1909 AN: 5144

South Asian (SAS) AF: 0.316 AC: 1513 AN: 4794

European-Finnish (FIN) AF: 0.333 AC: 3512 AN: 10540

Middle Eastern (MID) AF: 0.414 AC: 121 AN: 292

European-Non Finnish (NFE) AF: 0.363 AC: 24648 AN: 67944

Other (OTH) AF: 0.345 AC: 726 AN: 2102

Alfa AF: 0.346 Hom.: 15633

Bravo AF: 0.316

Asia WGS AF: 0.282 AC: 983 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.027
DANN	Benign	0.41
PhyloP100		-1.0
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: rs4481204; hg19: chr4-166359421;