Genetic Variant KNG1:c.673-1175T>C (chr3-186730370-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.673-1175T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 151,718 control chromosomes in the GnomAD database, including 4,272 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 0.23 ( 4272 hom., cov: 30)

Consequence

KNG1
NM_001102416.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0180

Publications

4 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=-0.95).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001102416.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KNG1	NM_001102416.3	MANE Select	c.673-1175T>C	intron	N/A	NP_001095886.1	P01042-1
KNG1	NM_000893.4		c.673-1175T>C	intron	N/A	NP_000884.1	P01042-2
KNG1	NM_001166451.2		c.565-1175T>C	intron	N/A	NP_001159923.1	P01042-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KNG1	ENST00000644859.2	MANE Select	c.673-1175T>C	intron	N/A	ENSP00000493985.1	P01042-1
KNG1	ENST00000287611.8	TSL:1	c.673-1175T>C	intron	N/A	ENSP00000287611.2	P01042-2
KNG1	ENST00000897809.1		c.703-1175T>C	intron	N/A	ENSP00000567868.1

Frequencies

GnomAD3 genomes

AF:

0.231

AC:

34959

AN:

151600

Hom.:

4277

Cov.:

show subpopulations

Gnomad AFR

AF:

0.163

Gnomad AMI

AF:

0.390

Gnomad AMR

AF:

0.201

Gnomad ASJ

AF:

0.255

Gnomad EAS

AF:

0.278

Gnomad SAS

AF:

0.344

Gnomad FIN

AF:

0.232

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.262

Gnomad OTH

AF:

0.249

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.230

AC:

34958

AN:

151718

Hom.:

4272

Cov.:

AF XY:

0.230

AC XY:

17041

AN XY:

74120

show subpopulations

African (AFR)

AF:

0.163

AC:

6748

AN:

41412

American (AMR)

AF:

0.201

AC:

3052

AN:

15206

Ashkenazi Jewish (ASJ)

AF:

0.255

AC:

884

AN:

3468

East Asian (EAS)

AF:

0.277

AC:

1427

AN:

5150

South Asian (SAS)

AF:

0.345

AC:

1652

AN:

4794

European-Finnish (FIN)

AF:

0.232

AC:

2433

AN:

10486

Middle Eastern (MID)

AF:

0.255

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.262

AC:

17809

AN:

67892

Other (OTH)

AF:

0.248

AC:

523

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

1336

2671

4007

5342

6678

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

370

740

1110

1480

1850

<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:

0.234

Hom.:

1374

Bravo

AF:

0.222

Asia WGS

AF:

0.300

AC:

1041

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

3.4

(source)

DANN

Benign

0.36

PhyloP100

-0.018

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over