4-186236896-G-GT

Position:

• chr4-186236896-G-GT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1 BS2

The NM_000892.5(KLKB1):​c.451dup​(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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 B:2
• Conservation: PhyloP100: 4.96

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLKB1	NM_000892.5	c.451dup	p.Ser151PhefsTer34	frameshift_variant	5/15	ENST00000264690.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLKB1	ENST00000264690.11	c.451dup	p.Ser151PhefsTer34	frameshift_variant	5/15	1	NM_000892.5	P1

Frequencies

GnomAD3 genomes AF: 0.00379 AC: 576 AN: 152108 Hom.: 1 Cov.: 32

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.: 0 AF XY: 0.000905 AC XY: 123 AN XY: 135896

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.: 4 Cov.: 32 AF XY: 0.000484 AC XY: 352 AN XY: 727174

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.: 1 Cov.: 32 AF XY: 0.00363 AC XY: 270 AN XY: 74424

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: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Benign:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2022	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) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	KLKB1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

KLKB1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 04, 2023

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 (Maak et al. 2009. PubMed ID: 19404525; Nazir and Pathare 2019. Hematol Transfus Int J. 2019;7(1):11-15 DOI: 10.15406/htij.2019.07.00197; Dasgupta et al. 2020. PubMed ID: 31984307; Barco et al. 2020. PubMed ID: 322022057; Adenaeuer et al. 2020. PubMed ID: 33073460; Abraham et al. 2021. PubMed ID: 34847617) 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 (Barco et al. 2020. PubMed ID: 322022057; 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

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 09, 2022

- -

Inherited prekallikrein deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 13, 2022

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

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

Other links and lift over

dbSNP: rs560588447; hg19: chr4-187158050;