Variant 4-186232208-GCCAGATGAGGTGCACATTCCACCCAAGGTGTTTGCTATTCAGTTTTCTTCCAGCAAGTTCAATCAATGACATGGAGAAAAGGTAAAAGTTGGTATTTCATTATTGGAGAAGCTGTTTTTCAAAACTGAATCAGTTTTGTGCAGAAAGGTGTAGTATAACTGAGAGTTCTTCCTCACACGGGGTTCAAGGACCAGCTTCAGCAAAATC-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000892.5(KLKB1):c.143_221+128del(p.Gln48fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

KLKB1
NM_000892.5 frameshift, splice_donor, splice_region, intron

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.36

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-186232208-GCCAGATGAGGTGCACATTCCACCCAAGGTGTTTGCTATTCAGTTTTCTTCCAGCAAGTTCAATCAATGACATGGAGAAAAGGTAAAAGTTGGTATTTCATTATTGGAGAAGCTGTTTTTCAAAACTGAATCAGTTTTGTGCAGAAAGGTGTAGTATAACTGAGAGTTCTTCCTCACACGGGGTTCAAGGACCAGCTTCAGCAAAATC-G is Pathogenic according to our data. Variant chr4-186232208-GCCAGATGAGGTGCACATTCCACCCAAGGTGTTTGCTATTCAGTTTTCTTCCAGCAAGTTCAATCAATGACATGGAGAAAAGGTAAAAGTTGGTATTTCATTATTGGAGAAGCTGTTTTTCAAAACTGAATCAGTTTTGTGCAGAAAGGTGTAGTATAACTGAGAGTTCTTCCTCACACGGGGTTCAAGGACCAGCTTCAGCAAAATC-G is described in ClinVar as [Pathogenic]. Clinvar id is 1803727.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-186232208-GCCAGATGAGGTGCACATTCCACCCAAGGTGTTTGCTATTCAGTTTTCTTCCAGCAAGTTCAATCAATGACATGGAGAAAAGGTAAAAGTTGGTATTTCATTATTGGAGAAGCTGTTTTTCAAAACTGAATCAGTTTTGTGCAGAAAGGTGTAGTATAACTGAGAGTTCTTCCTCACACGGGGTTCAAGGACCAGCTTCAGCAAAATC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLKB1	NM_000892.5 linkuse as main transcript	c.143_221+128del	p.Gln48fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	3/15	ENST00000264690.11	NP_000883.2	P03952A8K9A9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLKB1	ENST00000264690.11 linkuse as main transcript	c.143_221+128del	p.Gln48fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	3/15	1	NM_000892.5	ENSP00000264690.6		P03952
ENSG00000290316	ENST00000511608.5 linkuse as main transcript	c.284_362+128del	p.Gln95fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	3/15	5		ENSP00000426629.1		H0YAC1

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inherited prekallikrein deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 06, 2022

We identified this deletion, NM_000892.4(KLKB1):c.143_221+128del, in an Iranian family using medical exome sequencing (Barco et al. PMID: 32202057). One daughter presented with a severely prolonged aPTT due to prekallikrein (PK) deficiency (1.3% PK activity) and bleeding symptoms due to Bernard-Soulier syndrome (Shahverdi et al. PMID: 29043243). She was homozygous for the variant; their parents were both heterozygous. This deletion is not included in dbSNP and due to its rarity, correlation with phenotype, and clearly deleterious nature, we have classified this variant as pathogenic (ACMG guideline). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

No publications associated with this variant yet.