Genetic Variant KNG1:c.*1061T>C (chr3-186743392-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001102416.3(KNG1):c.*1061T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 322,296 control chromosomes in the GnomAD database, including 6,737 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.19 ( 2969 hom., cov: 33)

Exomes 𝑓: 0.20 ( 3768 hom. )

Consequence

KNG1
NM_001102416.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0300

Publications

12 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
KNG1	NM_001102416.3 link	c.*1061T>C	3_prime_UTR_variant	Exon 10 of 10	ENST00000644859.2	NP_001095886.1	P01042-1
KNG1	NM_000893.4 link	c.1204-313T>C	intron_variant	Intron 10 of 10		NP_000884.1	P01042-2
KNG1	NM_001166451.2 link	c.1096-313T>C	intron_variant	Intron 9 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.*1061T>C		3_prime_UTR_variant	Exon 10 of 10		NM_001102416.3	ENSP00000493985.1		P01042-1

Frequencies

GnomAD3 genomes

AF:

0.190

AC:

28961

AN:

152068

Hom.:

2970

Cov.:

show subpopulations

Gnomad AFR

AF:

0.120

Gnomad AMI

AF:

0.354

Gnomad AMR

AF:

0.200

Gnomad ASJ

AF:

0.196

Gnomad EAS

AF:

0.148

Gnomad SAS

AF:

0.207

Gnomad FIN

AF:

0.245

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.222

Gnomad OTH

AF:

0.186

GnomAD4 exome

AF:

0.203

AC:

34469

AN:

170110

Hom.:

3768

Cov.:

AF XY:

0.202

AC XY:

18127

AN XY:

89772

show subpopulations

African (AFR)

AF:

0.112

AC:

639

AN:

5720

American (AMR)

AF:

0.206

AC:

1595

AN:

7750

Ashkenazi Jewish (ASJ)

AF:

0.182

AC:

857

AN:

4702

East Asian (EAS)

AF:

0.133

AC:

1254

AN:

9424

South Asian (SAS)

AF:

0.196

AC:

4670

AN:

23776

European-Finnish (FIN)

AF:

0.235

AC:

1757

AN:

7482

Middle Eastern (MID)

AF:

0.219

AC:

140

AN:

638

European-Non Finnish (NFE)

AF:

0.213

AC:

21649

AN:

101458

Other (OTH)

AF:

0.208

AC:

1908

AN:

9160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1279

2558

3836

5115

6394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

170

340

510

680

850

<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:

0.190

AC:

28961

AN:

152186

Hom.:

2969

Cov.:

AF XY:

0.190

AC XY:

14160

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.120

AC:

4976

AN:

41544

American (AMR)

AF:

0.200

AC:

3051

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.196

AC:

679

AN:

3472

East Asian (EAS)

AF:

0.149

AC:

771

AN:

5184

South Asian (SAS)

AF:

0.206

AC:

995

AN:

4822

European-Finnish (FIN)

AF:

0.245

AC:

2590

AN:

10582

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.222

AC:

15121

AN:

67980

Other (OTH)

AF:

0.187

AC:

396

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1198

2397

3595

4794

5992

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

308

616

924

1232

1540

<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:

0.213

Hom.:

5744

Bravo

AF:

0.185

Asia WGS

AF:

0.183

AC:

637

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

5.0

(source)

DANN

Benign

0.86

PhyloP100

0.030

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

Computational scores

Splicing

Publications

Other links and lift over