4-186236880-G-C

Position:

• chr4-186236880-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000892.5(KLKB1):​c.428G>C​(p.Ser143Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S143N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: KLKB1 NM_000892.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.21

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLKB1	NM_000892.5	c.428G>C	p.Ser143Thr	missense_variant	5/15	ENST00000264690.11	NP_000883.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLKB1	ENST00000264690.11	c.428G>C	p.Ser143Thr	missense_variant	5/15	1	NM_000892.5	ENSP00000264690.6
ENSG00000290316	ENST00000511608.5	c.569G>C	p.Ser190Thr	missense_variant	5/15	5		ENSP00000426629.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.31	T;.;T;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.29	T;.;T;T
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.51	D;D;D;D
MetaSVM	Benign	-0.73	T
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.77	N;N;N;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0030	D;D;D;.
Sift4G	Uncertain	0.012	D;D;D;D
Vest4		0.30, 0.29
MutPred		0.54		Gain of ubiquitination at K139 (P = 0.0954);Gain of ubiquitination at K139 (P = 0.0954);.;.;
MVP		0.70
MPC		0.10
ClinPred		0.88	D
GERP RS		4.9
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs3733402; hg19: chr4-187158034;