rs374776365

Variant names:

• chr13-46064707-G-A
• rs374776365
• NM_001872.5:c.737C>T

Your query was ambiguous. Multiple possible variants found:

• chr13-46064707-G-A
• chr13-46064707-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001872.5(CPB2):​c.737C>T​(p.Ala246Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000638 in 1,613,884 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: CPB2 NM_001872.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.691
• Publications: 3 publications found

Genes affected

CPB2 (HGNC:2300): (carboxypeptidase B2) Carboxypeptidases are enzymes that hydrolyze C-terminal peptide bonds. The carboxypeptidase family includes metallo-, serine, and cysteine carboxypeptidases. According to their substrate specificity, these enzymes are referred to as carboxypeptidase A (cleaving aliphatic residues) or carboxypeptidase B (cleaving basic amino residues). The protein encoded by this gene is activated by trypsin and acts on carboxypeptidase B substrates. After thrombin activation, the mature protein downregulates fibrinolysis. Polymorphisms have been described for this gene and its promoter region. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jun 2013]

CPB2-AS1 (HGNC:39898): (CPB2 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053293854).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001872.5. 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
	CPB2	NM_001872.5	MANE Select	c.737C>T	p.Ala246Val	missense	Exon 8 of 11	NP_001863.3	Q96IY4-1
	CPB2	NM_001278541.2		c.626C>T	p.Ala209Val	missense	Exon 7 of 10	NP_001265470.1	A0A087WSY5
	CPB2-AS1	NR_046226.1		n.118+11742G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPB2	ENST00000181383.10	TSL:1 MANE Select	c.737C>T	p.Ala246Val	missense	Exon 8 of 11	ENSP00000181383.4	Q96IY4-1
	CPB2	ENST00000882332.1		c.839C>T	p.Ala280Val	missense	Exon 8 of 11	ENSP00000552391.1
	CPB2	ENST00000882315.1		c.785C>T	p.Ala262Val	missense	Exon 8 of 11	ENSP00000552374.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152158 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251450 AF XY: 0.0000662

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000588 AC: 86 AN: 1461726 Hom.: 0 Cov.: 30 AF XY: 0.0000633 AC XY: 46 AN XY: 727174

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

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

European-Non Finnish (NFE) AF: 0.0000576 AC: 64 AN: 1111922

Other (OTH) AF: 0.0000331 AC: 2 AN: 60386

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152158 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74334

African (AFR) AF: 0.000265 AC: 11 AN: 41432

American (AMR) AF: 0.000262 AC: 4 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.18
DANN	Benign	0.93
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.51	N
PhyloP100		-0.69
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.013
Sift	Benign	0.12	T
Sift4G	Benign	0.15	T
Polyphen		0.0030	B
Vest4		0.047
MVP		0.21
MPC		0.38
ClinPred		0.010	T
GERP RS		-5.8
Varity_R		0.17
gMVP		0.43
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs374776365; hg19: chr13-46638842; COSMIC: COSV51676148;