rs2304456

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001102416.3(KNG1):c.591T>G(p.Ile197Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,610,870 control chromosomes in the GnomAD database, including 11,734 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.095 ( 850 hom., cov: 32)

Exomes 𝑓: 0.12 ( 10884 hom. )

Consequence

KNG1
NM_001102416.3 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -1.48

Publications

49 publications found

Variant links:

Genes affected

KNG1 (HGNC:6383): (kininogen 1) This gene uses alternative splicing to generate two different proteins- high molecular weight kininogen (HMWK) and low molecular weight kininogen (LMWK). HMWK is essential for blood coagulation and assembly of the kallikrein-kinin system. Also, bradykinin, a peptide causing numerous physiological effects, is released from HMWK. Bradykinin also functions as an antimicrobial peptide with antibacterial and antifungal activity. In contrast to HMWK, LMWK is not involved in blood coagulation. Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reduces or depletes angiotensin converting enzyme 2 (ACE2), which results in an increase in levels of des-Arg(9)-bradykinin, a bioactive metabolite of bradykinin that is associated with lung injury and inflammation. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2020]

KNG1 links:

HRG-AS1 (HGNC:55915): (HRG and FETUB antisense RNA 1)

HRG-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006281644).

BP6

Variant 3-186727263-T-G is Benign according to our data. Variant chr3-186727263-T-G is described in ClinVar as Benign. ClinVar VariationId is 3038288.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNG1	NM_001102416.3 link	c.591T>G	p.Ile197Met	missense_variant	Exon 5 of 10	ENST00000644859.2	NP_001095886.1	P01042-1
KNG1	NM_000893.4 link	c.591T>G	p.Ile197Met	missense_variant	Exon 5 of 11		NP_000884.1	P01042-2
KNG1	NM_001166451.2 link	c.564+2003T>G		intron_variant	Intron 4 of 9		NP_001159923.1	P01042-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2 link	c.591T>G	p.Ile197Met	missense_variant	Exon 5 of 10		NM_001102416.3	ENSP00000493985.1		P01042-1

Frequencies

GnomAD3 genomes

AF:

0.0954

AC:

14520

AN:

152160

Hom.:

851

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0394

Gnomad AMI

AF:

0.128

Gnomad AMR

AF:

0.0809

Gnomad ASJ

AF:

0.110

Gnomad EAS

AF:

0.169

Gnomad SAS

AF:

0.230

Gnomad FIN

AF:

0.127

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.111

Gnomad OTH

AF:

0.104

GnomAD2 exomes

AF:

0.119

AC:

29955

AN:

251386

AF XY:

0.126

show subpopulations

Gnomad AFR exome

AF:

0.0365

Gnomad AMR exome

AF:

0.0662

Gnomad ASJ exome

AF:

0.106

Gnomad EAS exome

AF:

0.167

Gnomad FIN exome

AF:

0.132

Gnomad NFE exome

AF:

0.110

Gnomad OTH exome

AF:

0.123

GnomAD4 exome

AF:

0.116

AC:

168737

AN:

1458592

Hom.:

10884

Cov.:

AF XY:

0.119

AC XY:

86534

AN XY:

725894

show subpopulations

African (AFR)

AF:

0.0353

AC:

1181

AN:

33450

American (AMR)

AF:

0.0682

AC:

3048

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.108

AC:

2826

AN:

26110

East Asian (EAS)

AF:

0.156

AC:

6180

AN:

39666

South Asian (SAS)

AF:

0.217

AC:

18697

AN:

86162

European-Finnish (FIN)

AF:

0.130

AC:

6946

AN:

53418

Middle Eastern (MID)

AF:

0.132

AC:

761

AN:

5764

European-Non Finnish (NFE)

AF:

0.110

AC:

122172

AN:

1109068

Other (OTH)

AF:

0.115

AC:

6926

AN:

60232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

6402

12805

19207

25610

32012

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4504

9008

13512

18016

22520

<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

AF:

0.0953

AC:

14516

AN:

152278

Hom.:

850

Cov.:

AF XY:

0.0983

AC XY:

7320

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0393

AC:

1634

AN:

41558

American (AMR)

AF:

0.0808

AC:

1237

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.110

AC:

383

AN:

3470

East Asian (EAS)

AF:

0.169

AC:

876

AN:

5192

South Asian (SAS)

AF:

0.230

AC:

1111

AN:

4826

European-Finnish (FIN)

AF:

0.127

AC:

1350

AN:

10592

Middle Eastern (MID)

AF:

0.106

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.111

AC:

7557

AN:

68020

Other (OTH)

AF:

0.104

AC:

220

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

654

1309

1963

2618

3272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

352

528

704

880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.107

Hom.:

2597

Bravo

AF:

0.0861

TwinsUK

AF:

0.114

AC:

423

ALSPAC

AF:

0.112

AC:

431

ESP6500AA

AF:

0.0406

AC:

179

ESP6500EA

AF:

0.115

AC:

986

ExAC

AF:

0.120

AC:

14632

Asia WGS

AF:

0.185

AC:

640

AN:

3478

EpiCase

AF:

0.106

EpiControl

AF:

0.107

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

KNG1-related disorder

Benign:1

Nov 04, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

4.1

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.29

.;T;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.59

.;.;T;T

MetaRNN

Benign

0.0063

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

M;M;M;M

PhyloP100

-1.5

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.4

.;N;N;.

REVEL

Benign

0.094

Sift

Benign

0.079

.;T;D;.

Sift4G

Uncertain

0.0020

.;D;D;.

Polyphen

0.97

D;P;D;P

Vest4

0.16, 0.35

MPC

0.21

ClinPred

0.042

GERP RS

-10

Varity_R

0.13

gMVP

0.43

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over