13-46055809-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001872.5(CPB2):c.1040T>C(p.Ile347Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.724 in 1,595,210 control chromosomes in the GnomAD database, including 421,043 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.76 (44926 hom., cov: 32)
  • Exomes 𝑓: 0.72 (376117 hom.)
• Consequence: CPB2 NM_001872.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.873

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.329296E-7).
• BP6: Variant 13-46055809-A-G is Benign according to our data. Variant chr13-46055809-A-G is described in ClinVar as [Benign]. Clinvar id is 3058934.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPB2	NM_001872.5	c.1040T>C	p.Ile347Thr	missense_variant	10/11	ENST00000181383.10
CPB2-AS1	NR_046226.1	n.118+2844A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPB2	ENST00000181383.10	c.1040T>C	p.Ile347Thr	missense_variant	10/11	1	NM_001872.5	P1
CPB2-AS1	ENST00000663159.1	n.469+2844A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.764 AC: 116212 AN: 152012 Hom.: 44878 Cov.: 32

Gnomad AFR AF: 0.864

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.750

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.804

Gnomad SAS AF: 0.701

Gnomad FIN AF: 0.809

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.711

Gnomad OTH AF: 0.723

GnomAD3 exomes AF: 0.740 AC: 182894 AN: 247026 Hom.: 68323 AF XY: 0.731 AC XY: 97791 AN XY: 133694

Gnomad AFR exome AF: 0.868

Gnomad AMR exome AF: 0.795

Gnomad ASJ exome AF: 0.656

Gnomad EAS exome AF: 0.809

Gnomad SAS exome AF: 0.692

Gnomad FIN exome AF: 0.810

Gnomad NFE exome AF: 0.704

Gnomad OTH exome AF: 0.719

GnomAD4 exome AF: 0.720 AC: 1038535 AN: 1443080 Hom.: 376117 Cov.: 28 AF XY: 0.718 AC XY: 515617 AN XY: 718496

Gnomad4 AFR exome AF: 0.868

Gnomad4 AMR exome AF: 0.794

Gnomad4 ASJ exome AF: 0.653

Gnomad4 EAS exome AF: 0.830

Gnomad4 SAS exome AF: 0.694

Gnomad4 FIN exome AF: 0.807

Gnomad4 NFE exome AF: 0.708

Gnomad4 OTH exome AF: 0.719

GnomAD4 genome AF: 0.765 AC: 116316 AN: 152130 Hom.: 44926 Cov.: 32 AF XY: 0.769 AC XY: 57150 AN XY: 74354

Gnomad4 AFR AF: 0.864

Gnomad4 AMR AF: 0.749

Gnomad4 ASJ AF: 0.656

Gnomad4 EAS AF: 0.804

Gnomad4 SAS AF: 0.701

Gnomad4 FIN AF: 0.809

Gnomad4 NFE AF: 0.711

Gnomad4 OTH AF: 0.724

Alfa AF: 0.710 Hom.: 93578

Bravo AF: 0.764

ESP6500AA AF: 0.862 AC: 3800

ESP6500EA AF: 0.703 AC: 6045

ExAC AF: 0.741 AC: 89988

Asia WGS AF: 0.764 AC: 2652 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CPB2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.024
Dann	Benign	0.35
DEOGEN2	Benign	0.050	T;T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0031	N
MetaRNN	Benign	8.3e-7	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.70	N;N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.41	T
Polyphen		0.0	B;B;.
Vest4		0.013, 0.060
MPC		0.48
ClinPred		0.0072	T
GERP RS		-7.5
Varity_R		0.088
gMVP		0.61

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

LitVar

Other links and lift over

dbSNP: rs1926447; hg19: chr13-46629944; COSMIC: COSV51674065; COSMIC: COSV51674065;