chr10-100048769-C-T

Variant names:

• chr10-100048769-C-T
• rs1589470177
• NM_001308.3:c.1219G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001308.3(CPN1):​c.1219G>A​(p.Glu407Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPN1 NM_001308.3 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.93
• Publications: 0 publications found

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]

CPN1 Gene-Disease associations (from GenCC):

• carboxypeptidase N deficiency

  Inheritance: AR Classification: LIMITED Submitted by: Illumina, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11577299).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPN1	NM_001308.3	MANE Select	c.1219G>A	p.Glu407Lys	missense	Exon 8 of 9	NP_001299.1	P15169

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPN1	ENST00000370418.8	TSL:1 MANE Select	c.1219G>A	p.Glu407Lys	missense	Exon 8 of 9	ENSP00000359446.3	P15169
	CPN1	ENST00000877015.1		c.1219G>A	p.Glu407Lys	missense	Exon 8 of 9	ENSP00000547074.1
	CPN1	ENST00000877014.1		c.1207G>A	p.Glu403Lys	missense	Exon 8 of 9	ENSP00000547073.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	Hereditary angioedema with normal C1Inh (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.78
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.9
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.022
Sift	Benign	0.66	T
Sift4G	Benign	0.92	T
Polyphen		0.033	B
Vest4		0.27
MutPred		0.32		Gain of methylation at E407 (P = 0.0105)
MVP		0.34
MPC		0.46
ClinPred		0.12	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.61
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1589470177; hg19: chr10-101808526;