NM_001872.5:c.1040T>C

Variant names:

• chr13-46055809-A-G
• rs1926447
• NM_001872.5:c.1040T>C

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• 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
• Publications: 129 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: Benign. The variant received -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 VariationId 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.

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.1040T>C	p.Ile347Thr	missense	Exon 10 of 11	NP_001863.3	Q96IY4-1
	CPB2	NM_001278541.2		c.929T>C	p.Ile310Thr	missense	Exon 9 of 10	NP_001265470.1	A0A087WSY5
	CPB2-AS1	NR_046226.1		n.118+2844A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPB2	ENST00000181383.10	TSL:1 MANE Select	c.1040T>C	p.Ile347Thr	missense	Exon 10 of 11	ENSP00000181383.4	Q96IY4-1
	CPB2	ENST00000882332.1		c.1142T>C	p.Ile381Thr	missense	Exon 10 of 11	ENSP00000552391.1
	CPB2	ENST00000882315.1		c.1088T>C	p.Ile363Thr	missense	Exon 10 of 11	ENSP00000552374.1

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

GnomAD2 exomes AF: 0.740 AC: 182894 AN: 247026 AF XY: 0.731

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 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

African (AFR) AF: 0.868 AC: 28604 AN: 32970

American (AMR) AF: 0.794 AC: 34824 AN: 43854

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 16904 AN: 25868

East Asian (EAS) AF: 0.830 AC: 32565 AN: 39234

South Asian (SAS) AF: 0.694 AC: 58674 AN: 84566

European-Finnish (FIN) AF: 0.807 AC: 42652 AN: 52822

Middle Eastern (MID) AF: 0.644 AC: 3674 AN: 5708

European-Non Finnish (NFE) AF: 0.708 AC: 777736 AN: 1098354

Other (OTH) AF: 0.719 AC: 42902 AN: 59704

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

African (AFR) AF: 0.864 AC: 35865 AN: 41526

American (AMR) AF: 0.749 AC: 11450 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 2277 AN: 3472

East Asian (EAS) AF: 0.804 AC: 4158 AN: 5174

South Asian (SAS) AF: 0.701 AC: 3380 AN: 4820

European-Finnish (FIN) AF: 0.809 AC: 8545 AN: 10562

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.711 AC: 48325 AN: 67974

Other (OTH) AF: 0.724 AC: 1533 AN: 2116

Alfa AF: 0.719 Hom.: 187135

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

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CPB2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0031	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	8.3e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.70	N
PhyloP100		-0.87
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.066
Sift	Benign	0.69	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.013
MPC		0.48
ClinPred		0.0072	T
GERP RS		-7.5
Varity_R		0.088
gMVP		0.61
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

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