10-100065279-T-G

Variant names:

• chr10-100065279-T-G
• rs777954396
• NM_001308.3:c.668A>C

Variant summary

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

The NM_001308.3(CPN1):​c.668A>C​(p.Asn223Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N223S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CPN1 NM_001308.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.98
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.668A>C	p.Asn223Thr	missense	Exon 4 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.668A>C	p.Asn223Thr	missense	Exon 4 of 9	ENSP00000359446.3	P15169
	CPN1	ENST00000877015.1		c.668A>C	p.Asn223Thr	missense	Exon 4 of 9	ENSP00000547074.1
	CPN1	ENST00000877014.1		c.607A>C	p.Ile203Leu	missense	Exon 4 of 9	ENSP00000547073.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.27
Sift	Benign	0.23	T
Sift4G	Benign	0.27	T
Polyphen		1.0	D
Vest4		0.57
MutPred		0.58		Gain of glycosylation at N223 (P = 0.0539)
MVP		0.31
MPC		1.2
ClinPred		1.0	D
GERP RS		4.6
PromoterAI		-0.13	Neutral
Varity_R		0.72
gMVP		0.92
Mutation Taster		=9/91	disease causing

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

Other links and lift over

dbSNP: rs777954396; hg19: chr10-101825036;