13-46073959-C-T

Position:

• chr13-46073959-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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 (no stars). 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 no assertion criteria provided 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 -13 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 no_assertion_criteria_provided, 0 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	Protein	UniProt
CPB2	NM_001872.5	c.505G>A	p.Ala169Thr	missense_variant	6/11	ENST00000181383.10	NP_001863.3
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	Protein	Appris	UniProt
CPB2	ENST00000181383.10	c.505G>A	p.Ala169Thr	missense_variant	6/11	1	NM_001872.5	ENSP00000181383	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: no assertion criteria provided

Submissions by phenotype

CPB2-related disorder Benign:1

Benign, no assertion criteria provided

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
LIST_S2	Benign	0.040	.;T;T
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
PROVEAN	Benign	0.61	.;N;N
REVEL	Benign	0.024
Sift	Benign	0.61	.;T;T
Sift4G	Benign	0.68	.;T;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;