NM_000892.5:c.143_221+128del

Variant names:

• chr4-186232208-GCCAGATGAGGTGCACATTCCACCCAAGGTGTTTGCTATTCAGTTTTCTTCCAGCAAGTTCAATCAATGACATGGAGAAAAGGTAAAAGTTGGTATTTCATTATTGGAGAAGCTGTTTTTCAAAACTGAATCAGTTTTGTGCAGAAAGGTGTAGTATAACTGAGAGTTCTTCCTCACACGGGGTTCAAGGACCAGCTTCAGCAAAATC-G
• NM_000892.5:c.143_221+128del

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000892.5(KLKB1):​c.143_221+128del​(p.Gln48LysfsTer523) 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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.36

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]

ENSG00000290316 (HGNC:):

ACMG classification

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 rank	MANE	Protein	UniProt
KLKB1	NM_000892.5	c.143_221+128del	p.Gln48LysfsTer523	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 3 of 15	ENST00000264690.11	NP_000883.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLKB1	ENST00000264690.11	c.141_221+126del	p.Cys47_Arg74delinsTrp	splice_donor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	Exon 3 of 15	1	NM_000892.5	ENSP00000264690.6
ENSG00000290316	ENST00000511608.5	c.282_362+126del	p.Cys94_Arg121delinsTrp	splice_donor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	Exon 3 of 15	5		ENSP00000426629.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inherited prekallikrein deficiency Pathogenic:1

Dec 06, 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 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

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-187153362;