chr4-186258056-T-G

Variant names:

• chr4-186258056-T-G
• rs925453
• NM_000892.5:c.1761T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000892.5(KLKB1):​c.1761T>G​(p.Asn587Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N587N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLKB1 NM_000892.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.63
• Publications: 45 publications found

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)

ENSG00000290316 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13344187).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLKB1	NM_000892.5	c.1761T>G	p.Asn587Lys	missense_variant	Exon 15 of 15	ENST00000264690.11	NP_000883.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLKB1	ENST00000264690.11	c.1761T>G	p.Asn587Lys	missense_variant	Exon 15 of 15	1	NM_000892.5	ENSP00000264690.6
ENSG00000290316	ENST00000511608.5	c.1902T>G	p.Asn634Lys	missense_variant	Exon 15 of 15	5		ENSP00000426629.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 53

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 123394

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	0.0010
DANN	Benign	0.70
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.034	N
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.62	T
PhyloP100		-3.6
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.32
Sift	Benign	0.047	D
Sift4G	Benign	0.069	T
Vest4		0.18
MutPred		0.49		Gain of methylation at N587 (P = 0.0116);
MVP		0.49
MPC		0.13
ClinPred		0.11	T
GERP RS		-12
gMVP		0.34
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs925453; hg19: chr4-187179210;