chr4-186236880-G-C

Variant names:

• chr4-186236880-G-C
• rs3733402
• NM_000892.5:c.428G>C

Variant summary

Our verdict is Uncertain significance. The variant received 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. 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 Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: KLKB1 NM_000892.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.21
• Publications: 90 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 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000892.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLKB1	NM_000892.5	MANE Select	c.428G>C	p.Ser143Thr	missense	Exon 5 of 15	NP_000883.2
	KLKB1	NM_001440521.1		c.428G>C	p.Ser143Thr	missense	Exon 5 of 14	NP_001427450.1
	KLKB1	NM_001318394.2		c.314G>C	p.Ser105Thr	missense	Exon 6 of 15	NP_001305323.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLKB1	ENST00000264690.11	TSL:1 MANE Select	c.428G>C	p.Ser143Thr	missense	Exon 5 of 15	ENSP00000264690.6
	ENSG00000290316	ENST00000511608.5	TSL:5	c.569G>C	p.Ser190Thr	missense	Exon 5 of 15	ENSP00000426629.1
	KLKB1	ENST00000511406.5	TSL:1	n.458G>C		non_coding_transcript_exon	Exon 5 of 15

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.73	T
PhyloP100		4.2
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.77	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.012	D
Vest4		0.30
MutPred		0.54		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
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs3733402; hg19: chr4-187158034;