NM_001873.4:c.45A>T

Variant names:

• chr4-165379266-A-T
• rs757266004
• NM_001873.4:c.45A>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001873.4(CPE):​c.45A>T​(p.Ala15Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000077 in 1,298,992 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: CPE NM_001873.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.347

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP7: Synonymous conserved (PhyloP=-0.347 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPE	NM_001873.4	c.45A>T	p.Ala15Ala	synonymous_variant	Exon 1 of 9	ENST00000402744.9	NP_001864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPE	ENST00000402744.9	c.45A>T	p.Ala15Ala	synonymous_variant	Exon 1 of 9	1	NM_001873.4	ENSP00000386104.4
CPE	ENST00000513982.5	c.-30+17955A>T		intron_variant	Intron 1 of 3	4		ENSP00000424830.1
CPE	ENST00000480404.1	n.-20A>T		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000166 AC: 1 AN: 60200 Hom.: 0 AF XY: 0.0000301 AC XY: 1 AN XY: 33170

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000408

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.70e-7 AC: 1 AN: 1298992 Hom.: 0 Cov.: 31 AF XY: 0.00000157 AC XY: 1 AN XY: 637870

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.57e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.9
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs757266004; hg19: chr4-166300418;