chr4-165417176-A-G

Variant names:

• chr4-165417176-A-G
• rs28573326
• NM_001873.4:c.307+37648A>G

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+37648A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 151,960 control chromosomes in the GnomAD database, including 7,375 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 0.31 (7375 hom., cov: 31)
• Consequence: CPE NM_001873.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.97
• Publications: 2 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=-0.96).
• 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.307+37648A>G		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+37648A>G		intron_variant	Intron 1 of 8	1	NM_001873.4	ENSP00000386104.4
CPE	ENST00000431967.5	c.-30+1930A>G		intron_variant	Intron 1 of 3	4		ENSP00000416601.1
CPE	ENST00000513982.5	c.-29-47214A>G		intron_variant	Intron 1 of 3	4		ENSP00000424830.1

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47049 AN: 151842 Hom.: 7364 Cov.: 31

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.378

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.269

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.329

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

GnomAD4 genome AF: 0.310 AC: 47090 AN: 151960 Hom.: 7375 Cov.: 31 AF XY: 0.306 AC XY: 22748 AN XY: 74232

African (AFR) AF: 0.318 AC: 13176 AN: 41440

American (AMR) AF: 0.261 AC: 3982 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 1311 AN: 3470

East Asian (EAS) AF: 0.373 AC: 1920 AN: 5144

South Asian (SAS) AF: 0.297 AC: 1434 AN: 4824

European-Finnish (FIN) AF: 0.269 AC: 2832 AN: 10542

Middle Eastern (MID) AF: 0.408 AC: 119 AN: 292

European-Non Finnish (NFE) AF: 0.312 AC: 21215 AN: 67950

Other (OTH) AF: 0.332 AC: 699 AN: 2108

Alfa AF: 0.306 Hom.: 864

Bravo AF: 0.310

Asia WGS AF: 0.313 AC: 1090 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.44
DANN	Benign	0.73
PhyloP100		-2.0
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: rs28573326; hg19: chr4-166338328;