17-30379495-A-C

Position:

• chr17-30379495-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001304.5(CPD):​c.515A>C​(p.Asn172Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,421,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CPD NM_001304.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.79

Genes affected

CPD (HGNC:2301): (carboxypeptidase D) The metallocarboxypeptidase family of enzymes is divided into 2 subfamilies based on sequence similarities. The pancreatic carboxypeptidase-like and the regulatory B-type carboxypeptidase subfamilies. Carboxypeptidase D has been identified as a regulatory B-type carboxypeptidase. CPD is a homolog of duck gp180, a hepatitis B virus-binding protein. Transcript variants utilizing alternative polyadenylation signals exist for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity CBPD_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4081894).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPD	NM_001304.5	c.515A>C	p.Asn172Thr	missense_variant	1/21	ENST00000225719.9	NP_001295.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPD	ENST00000225719.9	c.515A>C	p.Asn172Thr	missense_variant	1/21	1	NM_001304.5	ENSP00000225719.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000155 AC: 22 AN: 1421292 Hom.: 0 Cov.: 33 AF XY: 0.0000141 AC XY: 10 AN XY: 706726

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: 0.0000191

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2023

The c.515A>C (p.N172T) alteration is located in exon 1 (coding exon 1) of the CPD gene. This alteration results from a A to C substitution at nucleotide position 515, causing the asparagine (N) at amino acid position 172 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.040	T
Eigen	Benign	0.068
Eigen_PC	Benign	0.042
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.11
Sift	Benign	0.26	T
Sift4G	Uncertain	0.0070	D
Polyphen		0.77	P
Vest4		0.41
MutPred		0.52		Loss of stability (P = 0.0788);
MVP		0.44
MPC		0.80
ClinPred		0.97	D
GERP RS		3.2
Varity_R		0.25
gMVP		0.59

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: rs1460795208; hg19: chr17-28706513;