4-186258056-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001440521.1(KLKB1):c.1621T>C(p.Trp541Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.68 in 1,613,544 control chromosomes in the GnomAD database, including 376,244 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.68 ( 35897 hom., cov: 32)

Exomes 𝑓: 0.68 ( 340347 hom. )

Consequence

KLKB1
NM_001440521.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.63

Publications

45 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=8.5759297E-7).

BP6

Variant 4-186258056-T-C is Benign according to our data. Variant chr4-186258056-T-C is described in ClinVar as Benign. ClinVar VariationId is 1273364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440521.1. 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.1761T>C	p.Asn587Asn	synonymous	Exon 15 of 15	NP_000883.2	P03952
KLKB1	NM_001440521.1		c.1621T>C	p.Trp541Arg	missense	Exon 14 of 14	NP_001427450.1
KLKB1	NM_001318394.2		c.1507T>C	p.Trp503Arg	missense	Exon 15 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.1761T>C	p.Asn587Asn	synonymous	Exon 15 of 15	ENSP00000264690.6	P03952
ENSG00000290316	ENST00000511608.5	TSL:5	c.1902T>C	p.Asn634Asn	synonymous	Exon 15 of 15	ENSP00000426629.1	H0YAC1
KLKB1	ENST00000511406.5	TSL:1	n.1822T>C		non_coding_transcript_exon	Exon 15 of 15

Frequencies

GnomAD3 genomes

AF:

0.685

AC:

104027

AN:

151898

Hom.:

35864

Cov.:

show subpopulations

Gnomad AFR

AF:

0.666

Gnomad AMI

AF:

0.795

Gnomad AMR

AF:

0.710

Gnomad ASJ

AF:

0.672

Gnomad EAS

AF:

0.857

Gnomad SAS

AF:

0.492

Gnomad FIN

AF:

0.700

Gnomad MID

AF:

0.756

Gnomad NFE

AF:

0.687

Gnomad OTH

AF:

0.704

GnomAD2 exomes

AF:

0.676

AC:

169885

AN:

251398

AF XY:

0.663

show subpopulations

Gnomad AFR exome

AF:

0.656

Gnomad AMR exome

AF:

0.727

Gnomad ASJ exome

AF:

0.666

Gnomad EAS exome

AF:

0.859

Gnomad FIN exome

AF:

0.696

Gnomad NFE exome

AF:

0.682

Gnomad OTH exome

AF:

0.698

GnomAD4 exome

AF:

0.679

AC:

992924

AN:

1461528

Hom.:

340347

Cov.:

AF XY:

0.672

AC XY:

488858

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.659

AC:

22066

AN:

33462

American (AMR)

AF:

0.725

AC:

32399

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.666

AC:

17402

AN:

26128

East Asian (EAS)

AF:

0.860

AC:

34155

AN:

39700

South Asian (SAS)

AF:

0.478

AC:

41266

AN:

86246

European-Finnish (FIN)

AF:

0.697

AC:

37256

AN:

53420

Middle Eastern (MID)

AF:

0.651

AC:

3752

AN:

5766

European-Non Finnish (NFE)

AF:

0.686

AC:

762886

AN:

1111714

Other (OTH)

AF:

0.691

AC:

41742

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

17548

35096

52643

70191

87739

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19466

38932

58398

77864

97330

<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:

0.685

AC:

104113

AN:

152016

Hom.:

35897

Cov.:

AF XY:

0.682

AC XY:

50692

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.666

AC:

27585

AN:

41430

American (AMR)

AF:

0.711

AC:

10857

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.672

AC:

2334

AN:

3472

East Asian (EAS)

AF:

0.857

AC:

4425

AN:

5164

South Asian (SAS)

AF:

0.492

AC:

2372

AN:

4824

European-Finnish (FIN)

AF:

0.700

AC:

7387

AN:

10546

Middle Eastern (MID)

AF:

0.748

AC:

220

AN:

294

European-Non Finnish (NFE)

AF:

0.687

AC:

46722

AN:

67988

Other (OTH)

AF:

0.706

AC:

1488

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1701

3401

5102

6802

8503

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

810

1620

2430

3240

4050

<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:

0.683

Hom.:

123394

Bravo

AF:

0.692

TwinsUK

AF:

0.687

AC:

2549

ALSPAC

AF:

0.675

AC:

2601

ESP6500AA

AF:

0.661

AC:

2914

ESP6500EA

AF:

0.687

AC:

5908

ExAC

AF:

0.668

AC:

81112

Asia WGS

AF:

0.665

AC:

2314

AN:

3478

EpiCase

AF:

0.679

EpiControl

AF:

0.683

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.89

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.0030

(source)

DANN

Benign

0.28

DEOGEN2

Benign

0.068

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.15

MetaRNN

Benign

8.6e-7

MetaSVM

Benign

-0.93

PhyloP100

-3.6

REVEL

Benign

0.28

Sift4G

Benign

0.14

Vest4

0.031

ClinPred

0.022

GERP RS

-12

Mutation Taster

=99/1

polymorphism (auto)

(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