Genetic Variant NM_000892.5:c.335A>C (chr4-186236787-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_000892.5(KLKB1):c.335A>C(p.His112Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,760 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

KLKB1
NM_000892.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.85

Publications

1 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

KLKB1 links:

ENSG00000290316 (HGNC:):

ENSG00000290316 links:

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ACMG classification

Classification was made for transcript

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

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLKB1	NM_000892.5	MANE Select	c.335A>C	p.His112Pro	missense	Exon 5 of 15	NP_000883.2	P03952
KLKB1	NM_001440521.1		c.335A>C	p.His112Pro	missense	Exon 5 of 14	NP_001427450.1
KLKB1	NM_001318394.2		c.221A>C	p.His74Pro	missense	Exon 6 of 15	NP_001305323.1	E9PBC5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLKB1	ENST00000264690.11	TSL:1 MANE Select	c.335A>C	p.His112Pro	missense	Exon 5 of 15	ENSP00000264690.6	P03952
ENSG00000290316	ENST00000511608.5	TSL:5	c.476A>C	p.His159Pro	missense	Exon 5 of 15	ENSP00000426629.1	H0YAC1
KLKB1	ENST00000511406.5	TSL:1	n.365A>C		non_coding_transcript_exon	Exon 5 of 15

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251338

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461760

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.000197

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111918

Other (OTH)

AF:

0.0000166

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000330

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.00098

BayesDel_noAF

Uncertain

0.040

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.72

Eigen

Benign

0.035

Eigen_PC

Benign

0.0019

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.60

M_CAP

Benign

0.031

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-0.96

PhyloP100

2.9

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.64

Sift

Benign

0.11

Sift4G

Uncertain

0.058

Vest4

0.73

MutPred

0.61

Gain of glycosylation at Y116 (P = 0.0071)

MVP

0.93

MPC

0.56

ClinPred

0.76

GERP RS

3.7

gMVP

0.70

Mutation Taster

=93/7

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over