4-186236896-G-GT

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PVS1BS1_SupportingBS2

The NM_000892.5(KLKB1):c.451dupT(p.Ser151PhefsTer34) variant causes a frameshift change. The variant allele was found at a frequency of 0.000834 in 1,613,982 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0038 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00052 ( 4 hom. )

Consequence

KLKB1
NM_000892.5 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5B:2

Conservation

PhyloP100: 4.96

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 links:

ENSG00000290316 (HGNC:):

ENSG00000290316 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00382 (581/152226) while in subpopulation AFR AF= 0.0132 (549/41540). AF 95% confidence interval is 0.0123. There are 1 homozygotes in gnomad4. There are 270 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLKB1	NM_000892.5 link	c.451dupT	p.Ser151PhefsTer34	frameshift_variant	Exon 5 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.451dupT	p.Ser151PhefsTer34	frameshift_variant	Exon 5 of 15	1	NM_000892.5	ENSP00000264690.6		P03952
ENSG00000290316	ENST00000511608.5 link	c.592dupT	p.Ser198fs	frameshift_variant	Exon 5 of 15	5		ENSP00000426629.1		H0YAC1

Frequencies

GnomAD3 genomes

AF:

0.00379

AC:

576

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00113

AC:

285

AN:

251434

Hom.:

AF XY:

0.000905

AC XY:

123

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.0140

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000317

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000523

AC:

765

AN:

1461756

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

352

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.0143

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000475

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000157

Gnomad4 OTH exome

AF:

0.000845

GnomAD4 genome

AF:

0.00382

AC:

581

AN:

152226

Hom.:

Cov.:

AF XY:

0.00363

AC XY:

270

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0132

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00189

Bravo

AF:

0.00417

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Benign:2

Jan 24, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PM3_strong, PVS1 -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 23, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34426522, 19404525, 31984307, 32202057, 34847617, 33073460) -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KLKB1: BS1, BS2 -

KLKB1-related disorder

Pathogenic:1

Jun 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The KLKB1 c.451dupT variant is predicted to result in a frameshift and premature protein termination (p.Ser151Phefs*34). This variant has been reported in the compound heterozygous and homozygous states in multiple individuals with prekallikrein deficiency (see, for example, Maak et al. 2009. PubMed ID: 19404525, described as a single basepair insertion at codon 149; Dasgupta et al. 2020. PubMed ID: 31984307, described as a single basepair insertion at codon 132; Adenaeuer et al. 2020. PubMed ID: 33073460) and has been reported to co-segregate with the disorder in at least one family (Maak et al. 2009. PubMed ID: 19404525). This variant is reported in 1.4% of alleles in individuals of African descent in gnomAD and is the variant primarily responsible for the elevated prevalence of prekallikrein deficiency in this subpopulation (Adenaeuer et al. 2020. PubMed ID: 33073460). Frameshift variants in KLKB1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Prekallikrein deficiency

Pathogenic:1

Aug 09, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inherited prekallikrein deficiency

Pathogenic:1

Dec 13, 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 were able to detect this variant, NM_000892.4(KLKB1):c.451dupT p.(Ser151Phefs*34), in homozygosity in three unrelated individuals with severe prekallikrein deficiency and prolonged aPTT (Barco et al. PMID: 32202057; Adenaeuer et al. PMID: 33073460) (<1% PK activity and antigen level). Functional assays of one individual were originally published by Nazir et al. (DOI: 10.15406/htij.2019.07.00197). This is a frameshift variant in exon 5, resulting in a premature stop codon and virtually no detectable prekallikrein activity or antigen (CRM-). Other known cases with KLKB1 c.451dupT in the literature: This variant was first identified in a homozygous case (urn:nbn:de:hebis:30-67544 (German doctoral thesis) and by Maak et al. in a compound heterozygous prekallikrein deficient individual (PMID: 19404525 (paper in German)). Homozygosity for this variant was also detected in an African American case (PMID: 31984307) and an Indian case with PK deficiency (PMID: 34847617)(both did not adhere to HGVS nomenclature, but depicted sequences match). In summary, this variant is to be classified as pathogenic (ACMG criteria) and leads to no detectable PK activity or antigen. It is rare in many ethnicities (0.1-0.6%) but reaches a MAF of 1-2% in several African collectives (dbSNP), making it by far the most frequent PK deficiency causing variant. This variant alone causes one case of PK deficiency in every ~7000 people in native African collectives and collectives of African origin studied (PMID: 33073460). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over