rs3742264

chr13-46073959-C-T

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.505G>A(p.Ala169Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 1,578,308 control chromosomes in the GnomAD database, including 83,515 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 0.34 (9111 hom., cov: 30)
  • Exomes 𝑓: 0.32 (74404 hom.)
• Consequence: CPB2 NM_001872.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.748

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=0.0023388267).
• BP6: Variant 13-46073959-C-T is Benign according to our data. Variant chr13-46073959-C-T is described in ClinVar as [Benign]. Clinvar id is 3059667.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPB2	NM_001872.5	c.505G>A	p.Ala169Thr	missense_variant	6/11	ENST00000181383.10
CPB2-AS1	NR_046226.1	n.119-20894C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPB2	ENST00000181383.10	c.505G>A	p.Ala169Thr	missense_variant	6/11	1	NM_001872.5	P1
CPB2-AS1	ENST00000663159.1	n.469+20994C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.343 AC: 51867 AN: 151216 Hom.: 9105 Cov.: 30

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.290

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.344

GnomAD3 exomes AF: 0.312 AC: 78096 AN: 250340 Hom.: 12551 AF XY: 0.308 AC XY: 41595 AN XY: 135262

Gnomad AFR exome AF: 0.387

Gnomad AMR exome AF: 0.288

Gnomad ASJ exome AF: 0.356

Gnomad EAS exome AF: 0.258

Gnomad SAS exome AF: 0.214

Gnomad FIN exome AF: 0.399

Gnomad NFE exome AF: 0.323

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.319 AC: 455760 AN: 1426978 Hom.: 74404 Cov.: 31 AF XY: 0.316 AC XY: 223469 AN XY: 706124

Gnomad4 AFR exome AF: 0.390

Gnomad4 AMR exome AF: 0.290

Gnomad4 ASJ exome AF: 0.348

Gnomad4 EAS exome AF: 0.257

Gnomad4 SAS exome AF: 0.215

Gnomad4 FIN exome AF: 0.393

Gnomad4 NFE exome AF: 0.324

Gnomad4 OTH exome AF: 0.320

GnomAD4 genome AF: 0.343 AC: 51903 AN: 151330 Hom.: 9111 Cov.: 30 AF XY: 0.343 AC XY: 25377 AN XY: 73894

Gnomad4 AFR AF: 0.390

Gnomad4 AMR AF: 0.324

Gnomad4 ASJ AF: 0.343

Gnomad4 EAS AF: 0.251

Gnomad4 SAS AF: 0.207

Gnomad4 FIN AF: 0.399

Gnomad4 NFE AF: 0.327

Gnomad4 OTH AF: 0.344

Alfa AF: 0.326 Hom.: 18291

Bravo AF: 0.337

TwinsUK AF: 0.316 AC: 1172

ALSPAC AF: 0.332 AC: 1278

ESP6500AA AF: 0.389 AC: 1714

ESP6500EA AF: 0.323 AC: 2782

ExAC AF: 0.310 AC: 37644

Asia WGS AF: 0.264 AC: 917 AN: 3478

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	0.065
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	8.3
Dann	Benign	0.78
DEOGEN2	Benign	0.047	T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00088	N
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.0	N;N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.32	T
Polyphen		0.0	B;B;.
Vest4		0.0090, 0.050
MPC		0.37
ClinPred		0.0018	T
GERP RS		2.7
Varity_R		0.15
gMVP		0.56

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: rs3742264; hg19: chr13-46648094; COSMIC: COSV51674355;