rs121964951

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PP3_ModeratePP5BS1_Supporting

The NM_000892.5(KLKB1):c.1643G>A(p.Cys548Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000726 in 1,602,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00075 ( 0 hom. )

Consequence

KLKB1
NM_000892.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 8.57

Publications

15 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: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.907

PP5

Variant 4-186257283-G-A is Pathogenic according to our data. Variant chr4-186257283-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12035.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00052 (79/151958) while in subpopulation NFE AF = 0.00104 (71/67986). AF 95% confidence interval is 0.000848. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLKB1	NM_000892.5 link	c.1643G>A	p.Cys548Tyr	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.1643G>A	p.Cys548Tyr	missense_variant	Exon 14 of 15	1	NM_000892.5	ENSP00000264690.6		P03952
ENSG00000290316	ENST00000511608.5 link	c.1784G>A	p.Cys595Tyr	missense_variant	Exon 14 of 15	5		ENSP00000426629.1		H0YAC1

Frequencies

GnomAD3 genomes

AF:

0.000520

AC:

AN:

151958

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00104

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000685

AC:

171

AN:

249744

AF XY:

0.000718

show subpopulations

Gnomad AFR exome

AF:

0.0000623

Gnomad AMR exome

AF:

0.000993

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00107

Gnomad OTH exome

AF:

0.00215

GnomAD4 exome

AF:

0.000747

AC:

1084

AN:

1450332

Hom.:

Cov.:

AF XY:

0.000743

AC XY:

536

AN XY:

721764

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33290

American (AMR)

AF:

0.000992

AC:

AN:

44342

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25880

East Asian (EAS)

AF:

0.00

AC:

AN:

39248

South Asian (SAS)

AF:

0.0000473

AC:

AN:

84566

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52846

Middle Eastern (MID)

AF:

0.000527

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.000884

AC:

977

AN:

1104608

Other (OTH)

AF:

0.000835

AC:

AN:

59862

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

148

198

247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

144

180

<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:

0.000520

AC:

AN:

151958

Hom.:

Cov.:

AF XY:

0.000391

AC XY:

AN XY:

74212

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41394

American (AMR)

AF:

0.000131

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00104

AC:

AN:

67986

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000660

Hom.:

Bravo

AF:

0.000544

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000750

AC:

Asia WGS

AF:

0.000290

AC:

AN:

3458

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Prekallikrein deficiency

Pathogenic:1

Dec 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Inherited prekallikrein deficiency

Pathogenic:1

Dec 09, 2022

Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

We have identified the variant NM_000892.4(KLKB1):c.1643G>A p.(Cys548Tyr) in three unrelated families, each with an index case of severe prekallikrein (PK) deficiency (Barco et al. PMID: 32202057). Family 1 comprises an index case homozygous for the above variant (<1% PK activity; 10% PK antigen; prolonged aPTT) and its heterozygous parents. The second family consists of a compound heterozygous index case carrying the above variant and the stop gained variant c.1196G>A p.(Trp399*) (<1% PK activity; 6-10% PK antigen; prolonged aPTT) and its daughter heterozygous for c.1643G>A (family first described in PMID: 8259543 as "PK Zurich"). The third case is a single compound heterozygous individual carrying the above variant and c.689T>A p.(Ile230Asn) (<1% PK activity; 9% PK antigen; prolonged aPTT) (first published in a PhD thesis: urn:nbn:de:hebis:30-67544 (in German)). Eight more cases have been reported in the literature by five authors (summarized in PMID: 32202057); some use the old nomenclature Cys529Tyr: Farac presents in her above mentioned PhD thesis two further compound heterozygous cases of Cys548Tyr (with c.451dupT and c.717_719delCTT, respectively) and one homozygous case. Dasanu et al. (PMID: 19773642) reported one, and Francois et al. (PMID: 17413767) two unrelated homozygous cases. Two other compound heterozygous cases are described by Maak et al (also with c.451dupT)(PMID: 19404525) and Lombardi et al (with c.1205G>A)(PMID: 14652634). All of these cases have in common that they have no PK activity (<1%) but, if measured, a residual antigen of 6-10% (CRM+). In addition, this variant has a global MAF of 0.03-0.08% (dbSNP) but reaches a MAF of 0.1% (GnomAD) among Europeans and Latinos, making it the most common PK deficiency-causing variant in these two collectives (Barco et al. PMID: 32202057). Based on all this, this variant is clearly pathogenic (ACMG criteria). -

not provided

Uncertain:1

May 08, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The C548Y variant in the KLKB1 gene has been reported previously in prekallikrein deficiency, in an individual with prolonged activated partial thromboplastin time who was compound heterozygous for the C548Y variant and another variant (Lombardi et al., 2003). The C548Y variant is observed in 19/11574 (0.16%) alleles from individuals of Latino background, and in 68/66574 (0.10%) alleles from individuals of Non-Finnish European background, in the ExAC dataset (Lek et al., 2016). The C548Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret C548Y as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

1.1

PhyloP100

8.6

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-9.4

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.93

MVP

0.98

MPC

0.71

ClinPred

0.93

GERP RS

5.8

gMVP

0.99

Mutation Taster

=3/97

disease causing

(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