4-165467673-C-CT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001873.4(CPE):c.505-3dup variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,195,554 control chromosomes in the GnomAD database, including 24 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (24 hom., cov: 32)
  • Exomes 𝑓: 0.025 (0 hom.)
• Consequence: CPE NM_001873.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.381

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 -16 ACMG points.

• BP6: Variant 4-165467673-C-CT is Benign according to our data. Variant chr4-165467673-C-CT is described in ClinVar as [Likely_benign]. Clinvar id is 1645773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPE	NM_001873.4	c.505-3dup		splice_polypyrimidine_tract_variant, intron_variant		ENST00000402744.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPE	ENST00000402744.9	c.505-3dup		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001873.4	P1
CPE	ENST00000431967.5	c.169-3dup		splice_polypyrimidine_tract_variant, intron_variant		4
CPE	ENST00000511992.1	c.169-3dup		splice_polypyrimidine_tract_variant, intron_variant		5
CPE	ENST00000513982.5	c.169-3dup		splice_polypyrimidine_tract_variant, intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1630 AN: 144812 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0356

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00685

Gnomad ASJ AF: 0.00446

Gnomad EAS AF: 0.000599

Gnomad SAS AF: 0.000438

Gnomad FIN AF: 0.00111

Gnomad MID AF: 0.0132

Gnomad NFE AF: 0.000945

Gnomad OTH AF: 0.0112

GnomAD4 exome AF: 0.0246 AC: 25887 AN: 1050712 Hom.: 0 Cov.: 0 AF XY: 0.0248 AC XY: 13016 AN XY: 524790

Gnomad4 AFR exome AF: 0.0641

Gnomad4 AMR exome AF: 0.0300

Gnomad4 ASJ exome AF: 0.0299

Gnomad4 EAS exome AF: 0.0245

Gnomad4 SAS exome AF: 0.0374

Gnomad4 FIN exome AF: 0.0210

Gnomad4 NFE exome AF: 0.0223

Gnomad4 OTH exome AF: 0.0267

GnomAD4 genome AF: 0.0113 AC: 1631 AN: 144842 Hom.: 24 Cov.: 32 AF XY: 0.0111 AC XY: 784 AN XY: 70426

Gnomad4 AFR AF: 0.0356

Gnomad4 AMR AF: 0.00671

Gnomad4 ASJ AF: 0.00446

Gnomad4 EAS AF: 0.000601

Gnomad4 SAS AF: 0.000659

Gnomad4 FIN AF: 0.00111

Gnomad4 NFE AF: 0.000946

Gnomad4 OTH AF: 0.0111

Bravo AF: 0.0123

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

BDV syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 14, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2024

- -

Computational scores

Source: dbNSFP v4.3

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: rs754217127; hg19: chr4-166388825;