rs1926447

Positions:

• chr13-46055809-A-G
• chr13-46055809-A-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.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 (no stars). 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 no assertion criteria provided 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 -13 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 no_assertion_criteria_provided, 0 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	Protein	UniProt
CPB2	NM_001872.5	c.1040T>C	p.Ile347Thr	missense_variant	10/11	ENST00000181383.10	NP_001863.3
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	Protein	Appris	UniProt
CPB2	ENST00000181383.10	c.1040T>C	p.Ile347Thr	missense_variant	10/11	1	NM_001872.5	ENSP00000181383	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: 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	0.091
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
LIST_S2	Benign	0.41	.;T;T
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
PROVEAN	Benign	-0.16	.;N;N
REVEL	Benign	0.066
Sift	Benign	0.69	.;T;T
Sift4G	Benign	0.44	.;T;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;