rs4253325

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000892.5(KLKB1):c.1679G>A(p.Arg560Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,601,918 control chromosomes in the GnomAD database, including 15,590 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2326 hom., cov: 32)

Exomes 𝑓: 0.12 ( 13264 hom. )

Consequence

KLKB1
NM_000892.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.59

Publications

29 publications found

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 Gene-Disease associations (from GenCC):

inherited prekallikrein deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

KLKB1 links:

ENSG00000290316 (HGNC:):

ENSG00000290316 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 4-186257319-G-A is Benign according to our data. Variant chr4-186257319-G-A is described in ClinVar as Benign. ClinVar VariationId is 1297284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLKB1	NM_000892.5 link	c.1679G>A	p.Arg560Gln	missense_variant	Exon 14 of 15	ENST00000264690.11	NP_000883.2	P03952A8K9A9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLKB1	ENST00000264690.11 link	c.1679G>A	p.Arg560Gln	missense_variant	Exon 14 of 15	1	NM_000892.5	ENSP00000264690.6		P03952
ENSG00000290316	ENST00000511608.5 link	c.1820G>A	p.Arg607Gln	missense_variant	Exon 14 of 15	5		ENSP00000426629.1		H0YAC1

Frequencies

GnomAD3 genomes

AF:

0.162

AC:

24646

AN:

151704

Hom.:

2327

Cov.:

show subpopulations

Gnomad AFR

AF:

0.234

Gnomad AMI

AF:

0.175

Gnomad AMR

AF:

0.198

Gnomad ASJ

AF:

0.151

Gnomad EAS

AF:

0.296

Gnomad SAS

AF:

0.228

Gnomad FIN

AF:

0.130

Gnomad MID

AF:

0.170

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.145

GnomAD2 exomes

AF:

0.165

AC:

41154

AN:

249108

AF XY:

0.161

show subpopulations

Gnomad AFR exome

AF:

0.234

Gnomad AMR exome

AF:

0.254

Gnomad ASJ exome

AF:

0.141

Gnomad EAS exome

AF:

0.306

Gnomad FIN exome

AF:

0.130

Gnomad NFE exome

AF:

0.100

Gnomad OTH exome

AF:

0.148

GnomAD4 exome

AF:

0.123

AC:

178163

AN:

1450098

Hom.:

13264

Cov.:

AF XY:

0.125

AC XY:

89969

AN XY:

721410

show subpopulations

African (AFR)

AF:

0.239

AC:

7937

AN:

33198

American (AMR)

AF:

0.248

AC:

10974

AN:

44186

Ashkenazi Jewish (ASJ)

AF:

0.139

AC:

3588

AN:

25866

East Asian (EAS)

AF:

0.294

AC:

11495

AN:

39154

South Asian (SAS)

AF:

0.218

AC:

18360

AN:

84314

European-Finnish (FIN)

AF:

0.124

AC:

6546

AN:

52800

Middle Eastern (MID)

AF:

0.164

AC:

935

AN:

5706

European-Non Finnish (NFE)

AF:

0.0995

AC:

109906

AN:

1105026

Other (OTH)

AF:

0.141

AC:

8422

AN:

59848

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

6901

13803

20704

27606

34507

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4432

8864

13296

17728

22160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.162

AC:

24669

AN:

151820

Hom.:

2326

Cov.:

AF XY:

0.166

AC XY:

12310

AN XY:

74202

show subpopulations

African (AFR)

AF:

0.234

AC:

9698

AN:

41380

American (AMR)

AF:

0.198

AC:

3015

AN:

15222

Ashkenazi Jewish (ASJ)

AF:

0.151

AC:

524

AN:

3472

East Asian (EAS)

AF:

0.296

AC:

1522

AN:

5150

South Asian (SAS)

AF:

0.227

AC:

1097

AN:

4822

European-Finnish (FIN)

AF:

0.130

AC:

1363

AN:

10484

Middle Eastern (MID)

AF:

0.169

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.102

AC:

6938

AN:

67982

Other (OTH)

AF:

0.144

AC:

304

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1012

2024

3036

4048

5060

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

272

544

816

1088

1360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.126

Hom.:

6462

Bravo

AF:

0.173

TwinsUK

AF:

0.0955

AC:

354

ALSPAC

AF:

0.102

AC:

392

ESP6500AA

AF:

0.227

AC:

998

ESP6500EA

AF:

0.107

AC:

920

ExAC

AF:

0.163

AC:

19776

Asia WGS

AF:

0.218

AC:

752

AN:

3462

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23413192, 25075649, 17318641, 32202057) -

KLKB1-related disorder

Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

0.058

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.81

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.041

MetaRNN

Benign

0.0082

MetaSVM

Benign

-1.1

PhyloP100

1.6

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.45

REVEL

Benign

0.28

Sift

Benign

0.50

Sift4G

Benign

0.45

Vest4

0.015

MPC

0.13

ClinPred

0.0011

GERP RS

2.1

gMVP

0.39

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.34

Position offset: 46

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over