4-186251858-T-G

Variant names:

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.1141T>G(p.Ser381Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,610,182 control chromosomes in the GnomAD database, including 12,136 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 923 hom., cov: 33)

Exomes 𝑓: 0.12 ( 11213 hom. )

Consequence

KLKB1
NM_000892.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.318

Publications

31 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001221925).

BP6

Variant 4-186251858-T-G is Benign according to our data. Variant chr4-186251858-T-G is described in ClinVar as Benign. ClinVar VariationId is 1238651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLKB1	NM_000892.5 link	c.1141T>G	p.Ser381Ala	missense_variant	Exon 10 of 15	ENST00000264690.11	NP_000883.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLKB1	ENST00000264690.11 link	c.1141T>G	p.Ser381Ala	missense_variant	Exon 10 of 15	1	NM_000892.5	ENSP00000264690.6
ENSG00000290316	ENST00000511608.5 link	c.1282T>G	p.Ser428Ala	missense_variant	Exon 10 of 15	5		ENSP00000426629.1

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15883

AN:

152170

Hom.:

924

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0600

Gnomad AMI

AF:

0.181

Gnomad AMR

AF:

0.107

Gnomad ASJ

AF:

0.0833

Gnomad EAS

AF:

0.0595

Gnomad SAS

AF:

0.203

Gnomad FIN

AF:

0.143

Gnomad MID

AF:

0.0605

Gnomad NFE

AF:

0.122

Gnomad OTH

AF:

0.0971

GnomAD2 exomes

AF:

0.120

AC:

30035

AN:

250684

AF XY:

0.126

show subpopulations

Gnomad AFR exome

AF:

0.0615

Gnomad AMR exome

AF:

0.0958

Gnomad ASJ exome

AF:

0.0937

Gnomad EAS exome

AF:

0.0620

Gnomad FIN exome

AF:

0.142

Gnomad NFE exome

AF:

0.123

Gnomad OTH exome

AF:

0.111

GnomAD4 exome

AF:

0.121

AC:

176808

AN:

1457894

Hom.:

11213

Cov.:

AF XY:

0.124

AC XY:

90161

AN XY:

725592

show subpopulations

African (AFR)

AF:

0.0591

AC:

1975

AN:

33416

American (AMR)

AF:

0.0949

AC:

4244

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0894

AC:

2335

AN:

26108

East Asian (EAS)

AF:

0.0640

AC:

2541

AN:

39682

South Asian (SAS)

AF:

0.195

AC:

16843

AN:

86176

European-Finnish (FIN)

AF:

0.144

AC:

7608

AN:

52928

Middle Eastern (MID)

AF:

0.120

AC:

689

AN:

5764

European-Non Finnish (NFE)

AF:

0.121

AC:

133730

AN:

1108832

Other (OTH)

AF:

0.114

AC:

6843

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

8273

16545

24818

33090

41363

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4812

9624

14436

19248

24060

<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:

0.104

AC:

15886

AN:

152288

Hom.:

923

Cov.:

AF XY:

0.108

AC XY:

8072

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0600

AC:

2496

AN:

41574

American (AMR)

AF:

0.107

AC:

1641

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0833

AC:

289

AN:

3468

East Asian (EAS)

AF:

0.0594

AC:

308

AN:

5184

South Asian (SAS)

AF:

0.203

AC:

977

AN:

4824

European-Finnish (FIN)

AF:

0.143

AC:

1515

AN:

10600

Middle Eastern (MID)

AF:

0.0651

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.122

AC:

8272

AN:

68016

Other (OTH)

AF:

0.0966

AC:

204

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

751

1502

2253

3004

3755

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

198

396

594

792

990

<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:

0.114

Hom.:

3670

Bravo

AF:

0.0963

TwinsUK

AF:

0.118

AC:

437

ALSPAC

AF:

0.128

AC:

495

ESP6500AA

AF:

0.0624

AC:

275

ESP6500EA

AF:

0.117

AC:

1004

ExAC

AF:

0.121

AC:

14741

Asia WGS

AF:

0.137

AC:

475

AN:

3478

EpiCase

AF:

0.126

EpiControl

AF:

0.124

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0

.;T

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.0

.;T

MetaRNN

Benign

0.0012

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.0

.;.

PhyloP100

0.32

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.73

N;.

REVEL

Benign

0.15

Sift

Benign

0.081

T;.

Sift4G

Benign

0.29

T;T

Vest4

0.11

ClinPred

0.00086

GERP RS

-2.6

gMVP

0.34

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over