4-186251266-C-T

Variant names:

• chr4-186251266-C-T
• rs4253376
• NM_000892.5:c.806C>T

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.806C>T​(p.Ser269Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S269C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KLKB1 NM_000892.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0910
• Publications: 0 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=0.087053865).

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.806C>T	p.Ser269Phe	missense	Exon 8 of 15	NP_000883.2
	KLKB1	NM_001440521.1		c.806C>T	p.Ser269Phe	missense	Exon 8 of 14	NP_001427450.1
	KLKB1	NM_001318394.2		c.692C>T	p.Ser231Phe	missense	Exon 9 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.806C>T	p.Ser269Phe	missense	Exon 8 of 15	ENSP00000264690.6
	ENSG00000290316	ENST00000511608.5	TSL:5	c.947C>T	p.Ser316Phe	missense	Exon 8 of 15	ENSP00000426629.1
	KLKB1	ENST00000511406.5	TSL:1	n.867C>T		non_coding_transcript_exon	Exon 8 of 15

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460300 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726546

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110702

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	9.9
DANN	Benign	0.50
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-0.64	T
PhyloP100		-0.091
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.29
Sift	Benign	0.72	T
Sift4G	Benign	0.46	T
Vest4		0.13
MutPred		0.36		Loss of glycosylation at P266 (P = 0.0095)
MVP		0.68
MPC		0.12
ClinPred		0.082	T
GERP RS		3.3
gMVP		0.36
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs4253376; hg19: chr4-187172420;