Variant 4-186236787-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000892.5(KLKB1):c.335A>C(p.His112Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,760 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

KLKB1
NM_000892.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.85

Variant links:

Genes affected

KLKB1 (HGNC:6371): (kallikrein B1) This gene encodes a glycoprotein that participates in the surface-dependent activation of blood coagulation, fibrinolysis, kinin generation and inflammation. The encoded preproprotein present in plasma as a non-covalent complex with high molecular weight kininogen undergoes proteolytic processing mediated by activated coagulation factor XII to generate a disulfide-linked, heterodimeric serine protease comprised of heavy and light chains. Certain mutations in this gene cause prekallikrein deficiency. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

KLKB1 links:

ENSG00000290316 (HGNC:):

ENSG00000290316 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLKB1	NM_000892.5 linkuse as main transcript	c.335A>C	p.His112Pro	missense_variant	5/15	ENST00000264690.11	NP_000883.2	P03952A8K9A9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLKB1	ENST00000264690.11 linkuse as main transcript	c.335A>C	p.His112Pro	missense_variant	5/15	1	NM_000892.5	ENSP00000264690.6		P03952
ENSG00000290316	ENST00000511608.5 linkuse as main transcript	c.476A>C	p.His159Pro	missense_variant	5/15	5		ENSP00000426629.1		H0YAC1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251338

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461760

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2023

The c.335A>C (p.H112P) alteration is located in exon 5 (coding exon 4) of the KLKB1 gene. This alteration results from a A to C substitution at nucleotide position 335, causing the histidine (H) at amino acid position 112 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.00098

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.72

D;.;D;D

Eigen

Benign

0.035

Eigen_PC

Benign

0.0019

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.60

T;.;T;T

M_CAP

Benign

0.031

MetaRNN

Uncertain

0.65

D;D;D;D

MetaSVM

Benign

-0.96

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.8

D;D;D;.

REVEL

Uncertain

0.64

Sift

Benign

0.11

T;D;T;.

Sift4G

Uncertain

0.058

T;D;T;D

Vest4

0.73, 0.66

MutPred

0.61

Gain of glycosylation at Y116 (P = 0.0071);Gain of glycosylation at Y116 (P = 0.0071);.;.;

MVP

0.93

MPC

0.56

ClinPred

0.76

GERP RS

3.7

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over