3-186743735-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBA1

The ENST00000287611.8(KNG1):c.1234C>T(p.Arg412*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0302 in 1,613,294 control chromosomes in the GnomAD database, including 1,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 53 hom., cov: 33)

Exomes 𝑓: 0.031 ( 963 hom. )

Consequence

KNG1
ENST00000287611.8 stop_gained

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.776

Publications

24 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 -14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0389 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

BP6

Variant 3-186743735-C-T is Benign according to our data. Variant chr3-186743735-C-T is described in ClinVar as Benign. ClinVar VariationId is 403021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNG1	NM_001102416.3 link	c.*1404C>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000644859.2	NP_001095886.1	P01042-1
KNG1	NM_000893.4 link	c.1234C>T	p.Arg412*	stop_gained	Exon 11 of 11		NP_000884.1	P01042-2
KNG1	NM_001166451.2 link	c.1126C>T	p.Arg376*	stop_gained	Exon 10 of 10		NP_001159923.1	P01042-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2 link	c.*1404C>T		3_prime_UTR_variant	Exon 10 of 10		NM_001102416.3	ENSP00000493985.1		P01042-1

Frequencies

GnomAD3 genomes

AF:

0.0199

AC:

3020

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00599

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0144

Gnomad ASJ

AF:

0.0395

Gnomad EAS

AF:

0.00770

Gnomad SAS

AF:

0.0743

Gnomad FIN

AF:

0.0103

Gnomad MID

AF:

0.0255

Gnomad NFE

AF:

0.0272

Gnomad OTH

AF:

0.0215

GnomAD2 exomes

AF:

0.0292

AC:

7325

AN:

250976

AF XY:

0.0335

show subpopulations

Gnomad AFR exome

AF:

0.00468

Gnomad AMR exome

AF:

0.00613

Gnomad ASJ exome

AF:

0.0416

Gnomad EAS exome

AF:

0.00995

Gnomad FIN exome

AF:

0.0136

Gnomad NFE exome

AF:

0.0303

Gnomad OTH exome

AF:

0.0278

GnomAD4 exome

AF:

0.0313

AC:

45681

AN:

1461038

Hom.:

963

Cov.:

AF XY:

0.0331

AC XY:

24090

AN XY:

726860

show subpopulations

African (AFR)

AF:

0.00338

AC:

113

AN:

33476

American (AMR)

AF:

0.00678

AC:

303

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0432

AC:

1128

AN:

26130

East Asian (EAS)

AF:

0.00688

AC:

273

AN:

39698

South Asian (SAS)

AF:

0.0830

AC:

7153

AN:

86230

European-Finnish (FIN)

AF:

0.0136

AC:

727

AN:

53416

Middle Eastern (MID)

AF:

0.0310

AC:

179

AN:

5766

European-Non Finnish (NFE)

AF:

0.0304

AC:

33738

AN:

1111246

Other (OTH)

AF:

0.0342

AC:

2067

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

2212

4424

6637

8849

11061

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1306

2612

3918

5224

6530

<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:

0.0198

AC:

3021

AN:

152256

Hom.:

Cov.:

AF XY:

0.0203

AC XY:

1508

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00597

AC:

248

AN:

41556

American (AMR)

AF:

0.0144

AC:

220

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0395

AC:

137

AN:

3468

East Asian (EAS)

AF:

0.00772

AC:

AN:

5182

South Asian (SAS)

AF:

0.0746

AC:

360

AN:

4826

European-Finnish (FIN)

AF:

0.0103

AC:

109

AN:

10604

Middle Eastern (MID)

AF:

0.0240

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0272

AC:

1853

AN:

68016

Other (OTH)

AF:

0.0218

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

156

312

468

624

780

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0262

Hom.:

216

Bravo

AF:

0.0185

TwinsUK

AF:

0.0307

AC:

114

ALSPAC

AF:

0.0246

AC:

ESP6500AA

AF:

0.00658

AC:

ESP6500EA

AF:

0.0274

AC:

236

ExAC

AF:

0.0312

AC:

3786

Asia WGS

AF:

0.0310

AC:

106

AN:

3478

EpiCase

AF:

0.0280

EpiControl

AF:

0.0276

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC frequency -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.093

Eigen_PC

Benign

-0.042

FATHMM_MKL

Benign

0.15

PhyloP100

0.78

Vest4

0.52, 0.46

GERP RS

4.1

Mutation Taster

=107/93

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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