Genetic Variant KNG1:c.195+872A>G (chr3-186718609-A-G) – 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.195+872A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 150,892 control chromosomes in the GnomAD database, including 9,276 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 0.34 ( 9262 hom., cov: 27)

Exomes 𝑓: 0.37 ( 14 hom. )

Consequence

KNG1
NM_001102416.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.539

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:

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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=-0.86).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
KNG1	NM_001102416.3 link	c.195+872A>G	intron_variant	Intron 1 of 9	ENST00000644859.2	NP_001095886.1
KNG1	NM_000893.4 link	c.195+872A>G	intron_variant	Intron 1 of 10		NP_000884.1
KNG1	NM_001166451.2 link	c.195+872A>G	intron_variant	Intron 1 of 9		NP_001159923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2 link	c.195+872A>G		intron_variant	Intron 1 of 9		NM_001102416.3	ENSP00000493985.1

Frequencies

GnomAD3 genomes

AF:

0.345

AC:

51922

AN:

150576

Hom.:

9259

Cov.:

show subpopulations

Gnomad AFR

AF:

0.413

Gnomad AMI

AF:

0.458

Gnomad AMR

AF:

0.284

Gnomad ASJ

AF:

0.275

Gnomad EAS

AF:

0.324

Gnomad SAS

AF:

0.433

Gnomad FIN

AF:

0.308

Gnomad MID

AF:

0.304

Gnomad NFE

AF:

0.322

Gnomad OTH

AF:

0.316

GnomAD4 exome

AF:

0.372

AC:

AN:

196

Hom.:

Cov.:

AF XY:

0.351

AC XY:

AN XY:

114

show subpopulations

African (AFR)

AF:

0.667

AC:

AN:

American (AMR)

AF:

0.500

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.360

AC:

AN:

150

Other (OTH)

AF:

0.167

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.345

AC:

51963

AN:

150696

Hom.:

9262

Cov.:

AF XY:

0.342

AC XY:

25154

AN XY:

73498

show subpopulations

African (AFR)

AF:

0.413

AC:

16898

AN:

40960

American (AMR)

AF:

0.284

AC:

4282

AN:

15088

Ashkenazi Jewish (ASJ)

AF:

0.275

AC:

952

AN:

3464

East Asian (EAS)

AF:

0.323

AC:

1618

AN:

5012

South Asian (SAS)

AF:

0.433

AC:

2060

AN:

4762

European-Finnish (FIN)

AF:

0.308

AC:

3202

AN:

10380

Middle Eastern (MID)

AF:

0.307

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.322

AC:

21788

AN:

67748

Other (OTH)

AF:

0.316

AC:

661

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1608

3215

4823

6430

8038

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

514

1028

1542

2056

2570

<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:

0.318

Hom.:

11393

Bravo

AF:

0.342

Asia WGS

AF:

0.389

AC:

1350

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

8.6

(source)

DANN

Benign

0.70

PhyloP100

0.54

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