rs3733402

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely 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/Likely benign criteria provided, multiple submitters, no conflicts P:1B:8

Conservation

PhyloP100: 4.21

Publications

90 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

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 -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/Likely_benign. ClinVar VariationId is 12037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000892.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLKB1	NM_000892.5	MANE Select	c.428G>A	p.Ser143Asn	missense	Exon 5 of 15	NP_000883.2	P03952
KLKB1	NM_001440521.1		c.428G>A	p.Ser143Asn	missense	Exon 5 of 14	NP_001427450.1
KLKB1	NM_001318394.2		c.314G>A	p.Ser105Asn	missense	Exon 6 of 15	NP_001305323.1	E9PBC5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLKB1	ENST00000264690.11	TSL:1 MANE Select	c.428G>A	p.Ser143Asn	missense	Exon 5 of 15	ENSP00000264690.6	P03952
ENSG00000290316	ENST00000511608.5	TSL:5	c.569G>A	p.Ser190Asn	missense	Exon 5 of 15	ENSP00000426629.1	H0YAC1
KLKB1	ENST00000511406.5	TSL:1	n.458G>A		non_coding_transcript_exon	Exon 5 of 15

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

GnomAD2 exomes

AF:

0.540

AC:

135782

AN:

251352

AF XY:

0.525

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 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

African (AFR)

AF:

0.739

AC:

24748

AN:

33476

American (AMR)

AF:

0.623

AC:

27848

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.439

AC:

11462

AN:

26132

East Asian (EAS)

AF:

0.643

AC:

25518

AN:

39690

South Asian (SAS)

AF:

0.392

AC:

33795

AN:

86236

European-Finnish (FIN)

AF:

0.575

AC:

30694

AN:

53416

Middle Eastern (MID)

AF:

0.481

AC:

2774

AN:

5768

European-Non Finnish (NFE)

AF:

0.510

AC:

567329

AN:

1111504

Other (OTH)

AF:

0.532

AC:

32088

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

19090

38180

57270

76360

95450

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16484

32968

49452

65936

82420

<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:

0.588

AC:

89276

AN:

151930

Hom.:

27094

Cov.:

AF XY:

0.587

AC XY:

43554

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.738

AC:

30625

AN:

41482

American (AMR)

AF:

0.585

AC:

8922

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.444

AC:

1539

AN:

3468

East Asian (EAS)

AF:

0.680

AC:

3501

AN:

5148

South Asian (SAS)

AF:

0.401

AC:

1924

AN:

4800

European-Finnish (FIN)

AF:

0.582

AC:

6131

AN:

10530

Middle Eastern (MID)

AF:

0.551

AC:

162

AN:

294

European-Non Finnish (NFE)

AF:

0.511

AC:

34726

AN:

67930

Other (OTH)

AF:

0.568

AC:

1196

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1773

3546

5318

7091

8864

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

744

1488

2232

2976

3720

<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:

0.533

Hom.:

56808

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Prekallikrein deficiency (2)

Hypophosphatemic rickets and hyperparathyroidism (1)

Inherited prekallikrein deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

7.3

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.21

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.0011

LIST_S2

Benign

0.081

MetaRNN

Benign

0.0000039

MetaSVM

Benign

-1.0

PhyloP100

4.2

PrimateAI

Benign

0.44

PROVEAN

Benign

2.4

REVEL

Benign

0.22

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.22

MPC

0.10

ClinPred

0.0033

GERP RS

4.9

gMVP

0.081

Mutation Taster

=99/1

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over