NM_001102416.3:c.586C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001102416.3(KNG1):c.586C>T(p.Arg196*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,612,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

KNG1
NM_001102416.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 0.134

Publications

3 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: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-186727258-C-T is Pathogenic according to our data. Variant chr3-186727258-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 572.Status of the report is criteria_provided_single_submitter, 1 stars.

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	HGVSp	Effect	Exon Rank	Protein
KNG1	NM_001102416.3	MANE Select	c.586C>T	p.Arg196*	stop_gained	Exon 5 of 10	NP_001095886.1
KNG1	NM_000893.4		c.586C>T	p.Arg196*	stop_gained	Exon 5 of 11	NP_000884.1
KNG1	NM_001166451.2		c.564+1998C>T		intron	N/A	NP_001159923.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KNG1	ENST00000644859.2	MANE Select	c.586C>T	p.Arg196*	stop_gained	Exon 5 of 10	ENSP00000493985.1
KNG1	ENST00000287611.8	TSL:1	c.586C>T	p.Arg196*	stop_gained	Exon 5 of 11	ENSP00000287611.2
KNG1	ENST00000447445.1	TSL:3	c.564+1998C>T		intron	N/A	ENSP00000396025.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251400

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1460772

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726800

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1111024

Other (OTH)

AF:

0.0000166

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000131

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41418

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000192

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.0000359

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

KININOGEN DEFICIENCY, TOTAL

Pathogenic:1

Nov 05, 1993

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

High molecular weight kininogen deficiency

Pathogenic:1

Sep 04, 2023

Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

We identified this variant, NM_001102416.3(KNG1):c.586C>T (p.Arg196*) in homozygosity as the cause of high-molecular-weight kininogen deficiency in an individual (<1% HK activity, prolonged aPTT) (PMID: 36700498). Large deletions were excluded via ddPCR. The case was originally described by Nazir et al (DOI: 10.15406/htij.2019.07.00197). The c.586C>T variant is the first and most frequently reported HK deficiency-causing variant in the literature. It has been described in three unrelated homozygous literature cases: it was first identified by Cheung et al. (PMID: 7901207) and also described by Ishimaru et al. (PMID. 10071463) and Nakamura et al. (PMID: 3853954). All three literature cases have barely measurable HK levels (<1% HK activity and antigen) and also very low to barely detectable levels of low-molecular-weight kininogen (LK), thus this variant results in combined HK and LK deficiency. The MAF of this variant is 0.001-0.007% (dbSNP). Therefore, we classified this variant as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Benign

0.96

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.015

PhyloP100

0.13

Vest4

0.79

GERP RS

-4.8

Mutation Taster

=7/193

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over