10-100065249-C-G

Variant names:

• chr10-100065249-C-G
• NM_001308.3:c.698G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001308.3(CPN1):​c.698G>C​(p.Arg233Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPN1 NM_001308.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.28

Genes affected

CPN1 (HGNC:2312): (carboxypeptidase N subunit 1) Carboxypeptidase N is a plasma metallo-protease that cleaves basic amino acids from the C terminal of peptides and proteins. The enzyme is important in the regulation of peptides like kinins and anaphylatoxins, and has also been known as kininase-1 and anaphylatoxin inactivator. This enzyme is a tetramer comprised of two identical regulatory subunits and two identical catalytic subunits; this gene encodes the catalytic subunit. Mutations in this gene can be associated with angioedema or chronic urticaria resulting from carboxypeptidase N deficiency. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2503847).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPN1	NM_001308.3	c.698G>C	p.Arg233Pro	missense_variant	Exon 4 of 9	ENST00000370418.8	NP_001299.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPN1	ENST00000370418.8	c.698G>C	p.Arg233Pro	missense_variant	Exon 4 of 9	1	NM_001308.3	ENSP00000359446.3
CPN1	ENST00000441382.1	c.89G>C	p.Arg30Pro	missense_variant	Exon 1 of 5	2		ENSP00000410895.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.698G>C (p.R233P) alteration is located in exon 4 (coding exon 4) of the CPN1 gene. This alteration results from a G to C substitution at nucleotide position 698, causing the arginine (R) at amino acid position 233 to be replaced by a proline (P). 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	Benign	0.29
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.67	N;N
REVEL	Benign	0.19
Sift	Benign	0.14	T;T
Sift4G	Benign	0.41	T;T
Polyphen		0.0040	B;.
Vest4		0.38
MutPred		0.59		Loss of MoRF binding (P = 0.0181);.;
MVP		0.35
MPC		0.59
ClinPred		0.53	D
GERP RS		3.7
Varity_R		0.57
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-101825006;