4-186236880-G-A

Position:

chr4-186236880-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000892.5(KLKB1):c.428G>A(p.Ser143Asn) variant causes a missense change. The variant allele was found at a frequency of 0.524 in 1,613,244 control chromosomes in the GnomAD database, including 226,077 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.59 ( 27094 hom., cov: 30)

Exomes 𝑓: 0.52 ( 198983 hom. )

Consequence

KLKB1
NM_000892.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:6

Conservation

PhyloP100: 4.21

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.8795765E-6).

BP6

Variant 4-186236880-G-A is Benign according to our data. Variant chr4-186236880-G-A is described in ClinVar as [Benign]. Clinvar id is 12037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186236880-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLKB1	NM_000892.5 linkuse as main transcript	c.428G>A	p.Ser143Asn	missense_variant	5/15	ENST00000264690.11	NP_000883.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLKB1	ENST00000264690.11 linkuse as main transcript	c.428G>A	p.Ser143Asn	missense_variant	5/15	1	NM_000892.5	ENSP00000264690	P1

Frequencies

GnomAD3 genomes

AF:

0.587

AC:

89168

AN:

151810

Hom.:

27042

Cov.:

show subpopulations

Gnomad AFR

AF:

0.738

Gnomad AMI

AF:

0.603

Gnomad AMR

AF:

0.584

Gnomad ASJ

AF:

0.444

Gnomad EAS

AF:

0.681

Gnomad SAS

AF:

0.400

Gnomad FIN

AF:

0.582

Gnomad MID

AF:

0.547

Gnomad NFE

AF:

0.511

Gnomad OTH

AF:

0.567

GnomAD3 exomes

AF:

0.540

AC:

135782

AN:

251352

Hom.:

37996

AF XY:

0.525

AC XY:

71298

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.736

Gnomad AMR exome

AF:

0.629

Gnomad ASJ exome

AF:

0.436

Gnomad EAS exome

AF:

0.671

Gnomad SAS exome

AF:

0.394

Gnomad FIN exome

AF:

0.578

Gnomad NFE exome

AF:

0.506

Gnomad OTH exome

AF:

0.537

GnomAD4 exome

AF:

0.518

AC:

756256

AN:

1461314

Hom.:

198983

Cov.:

AF XY:

0.512

AC XY:

371965

AN XY:

726952

show subpopulations

Gnomad4 AFR exome

AF:

0.739

Gnomad4 AMR exome

AF:

0.623

Gnomad4 ASJ exome

AF:

0.439

Gnomad4 EAS exome

AF:

0.643

Gnomad4 SAS exome

AF:

0.392

Gnomad4 FIN exome

AF:

0.575

Gnomad4 NFE exome

AF:

0.510

Gnomad4 OTH exome

AF:

0.532

GnomAD4 genome

AF:

0.588

AC:

89276

AN:

151930

Hom.:

27094

Cov.:

AF XY:

0.587

AC XY:

43554

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.738

Gnomad4 AMR

AF:

0.585

Gnomad4 ASJ

AF:

0.444

Gnomad4 EAS

AF:

0.680

Gnomad4 SAS

AF:

0.401

Gnomad4 FIN

AF:

0.582

Gnomad4 NFE

AF:

0.511

Gnomad4 OTH

AF:

0.568

Alfa

AF:

0.522

Hom.:

36509

Bravo

AF:

0.599

TwinsUK

AF:

0.526

AC:

1950

ALSPAC

AF:

0.502

AC:

1933

ESP6500AA

AF:

0.736

AC:

3245

ESP6500EA

AF:

0.507

AC:

4357

ExAC

AF:

0.536

AC:

65105

Asia WGS

AF:

0.532

AC:

1851

AN:

3478

EpiCase

AF:

0.499

EpiControl

AF:

0.499

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	research	H3Africa Consortium	Oct 28, 2020	While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.729, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Prekallikrein deficiency

Pathogenic:1Benign:1

Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000892.3:c.428G>A (Ser143Asn) in the KLKB1 gene has an allele frequency of 0.738 in African subpopulation in the gnomAD database, including 43762 homozygous events. Ser143Asn was reported as N124S according to ClinVar's annotation. Katsuda et al reported three Japanese patients with plasma prekallikrein deficiency, who harbors homozygousity of Gly104Arg and Asn124Ser in 2007. Co-segregate analysis demonstrate the proband's parents were heterozygous of Gly104Arg Asn124-Ser\Gly104Arg+ (PMID: 17598838). Considering the high frequency of this variant, we classify the variant as benign. ACMG/AMP criteria applied: BA1, BS2. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2007	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 20981092, 24625756, 23251661, 17598838, 28508493, 28492530) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

7.3

DANN

Benign

0.17

DEOGEN2

Benign

0.21

T;.;T;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.0011

LIST_S2

Benign

0.081

T;.;T;T

MetaRNN

Benign

0.0000039

T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.44

PROVEAN

Benign

2.4

N;N;N;.

REVEL

Benign

0.22

Sift

Benign

1.0

T;T;T;.

Sift4G

Benign

1.0

T;T;T;T

Vest4

0.22, 0.21

MPC

0.10

ClinPred

0.0033

GERP RS

4.9

gMVP

0.081

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

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