10-100065306-T-G

Variant names:

• chr10-100065306-T-G
• rs757428196
• NM_001308.3:c.641A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001308.3(CPN1):​c.641A>C​(p.Asn214Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. N214S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPN1 NM_001308.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.00
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

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.641A>C	p.Asn214Thr	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.641A>C	p.Asn214Thr	missense	Exon 4 of 9	ENSP00000359446.3	P15169
	CPN1	ENST00000877015.1		c.641A>C	p.Asn214Thr	missense	Exon 4 of 9	ENSP00000547074.1
	CPN1	ENST00000877014.1		c.580A>C	p.Ile194Leu	missense	Exon 4 of 9	ENSP00000547073.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251448 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		8.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.85		Loss of stability (P = 0.0368)
MVP		0.47
MPC		1.2
ClinPred		1.0	D
GERP RS		4.6
PromoterAI		-0.016	Neutral
Varity_R		0.91
gMVP		0.92
Mutation Taster		=8/92	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: rs757428196; hg19: chr10-101825063;