Variant 4-186251858-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000892.5(KLKB1):c.1141T>G(p.Ser381Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,610,182 control chromosomes in the GnomAD database, including 12,136 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.10 ( 923 hom., cov: 33)

Exomes 𝑓: 0.12 ( 11213 hom. )

Consequence

KLKB1
NM_000892.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.318

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001221925).

BP6

Variant 4-186251858-T-G is Benign according to our data. Variant chr4-186251858-T-G is described in ClinVar as [Benign]. Clinvar id is 1238651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLKB1	NM_000892.5 linkuse as main transcript	c.1141T>G	p.Ser381Ala	missense_variant	10/15	ENST00000264690.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
KLKB1	ENST00000264690.11 linkuse as main transcript	c.1141T>G	p.Ser381Ala	missense_variant	10/15	1	NM_000892.5	P1
KLKB1	ENST00000511406.5 linkuse as main transcript	n.1202T>G		non_coding_transcript_exon_variant	10/15	1
KLKB1	ENST00000513864.2 linkuse as main transcript	c.1027T>G	p.Ser343Ala	missense_variant	11/15	2
KLKB1	ENST00000467271.1 linkuse as main transcript	n.570T>G		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15883

AN:

152170

Hom.:

924

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0600

Gnomad AMI

AF:

0.181

Gnomad AMR

AF:

0.107

Gnomad ASJ

AF:

0.0833

Gnomad EAS

AF:

0.0595

Gnomad SAS

AF:

0.203

Gnomad FIN

AF:

0.143

Gnomad MID

AF:

0.0605

Gnomad NFE

AF:

0.122

Gnomad OTH

AF:

0.0971

GnomAD3 exomes

AF:

0.120

AC:

30035

AN:

250684

Hom.:

2010

AF XY:

0.126

AC XY:

17081

AN XY:

135560

show subpopulations

Gnomad AFR exome

AF:

0.0615

Gnomad AMR exome

AF:

0.0958

Gnomad ASJ exome

AF:

0.0937

Gnomad EAS exome

AF:

0.0620

Gnomad SAS exome

AF:

0.197

Gnomad FIN exome

AF:

0.142

Gnomad NFE exome

AF:

0.123

Gnomad OTH exome

AF:

0.111

GnomAD4 exome

AF:

0.121

AC:

176808

AN:

1457894

Hom.:

11213

Cov.:

AF XY:

0.124

AC XY:

90161

AN XY:

725592

show subpopulations

Gnomad4 AFR exome

AF:

0.0591

Gnomad4 AMR exome

AF:

0.0949

Gnomad4 ASJ exome

AF:

0.0894

Gnomad4 EAS exome

AF:

0.0640

Gnomad4 SAS exome

AF:

0.195

Gnomad4 FIN exome

AF:

0.144

Gnomad4 NFE exome

AF:

0.121

Gnomad4 OTH exome

AF:

0.114

GnomAD4 genome

AF:

0.104

AC:

15886

AN:

152288

Hom.:

923

Cov.:

AF XY:

0.108

AC XY:

8072

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0600

Gnomad4 AMR

AF:

0.107

Gnomad4 ASJ

AF:

0.0833

Gnomad4 EAS

AF:

0.0594

Gnomad4 SAS

AF:

0.203

Gnomad4 FIN

AF:

0.143

Gnomad4 NFE

AF:

0.122

Gnomad4 OTH

AF:

0.0966

Alfa

AF:

0.117

Hom.:

2749

Bravo

AF:

0.0963

TwinsUK

AF:

0.118

AC:

437

ALSPAC

AF:

0.128

AC:

495

ESP6500AA

AF:

0.0624

AC:

275

ESP6500EA

AF:

0.117

AC:

1004

ExAC

AF:

0.121

AC:

14741

Asia WGS

AF:

0.137

AC:

475

AN:

3478

EpiCase

AF:

0.126

EpiControl

AF:

0.124

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.094

.;T

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.45

.;T

MetaRNN

Benign

0.0012

T;T

MetaSVM

Benign

-0.90

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.73

N;.

REVEL

Benign

0.15

Sift

Benign

0.081

T;.

Sift4G

Benign

0.29

T;T

Vest4

0.11

MPC

0.098

ClinPred

0.00086

GERP RS

-2.6

gMVP

0.34

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over