3-186727258-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PP5_Moderate

The NM_001102416.3(KNG1):c.586C>T(p.Arg196Ter) 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

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 made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

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

PP5

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KNG1	NM_001102416.3 linkuse as main transcript	c.586C>T	p.Arg196Ter	stop_gained	5/10	ENST00000644859.2
KNG1	NM_000893.4 linkuse as main transcript	c.586C>T	p.Arg196Ter	stop_gained	5/11
KNG1	NM_001166451.2 linkuse as main transcript	c.564+1998C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNG1	ENST00000644859.2 linkuse as main transcript	c.586C>T	p.Arg196Ter	stop_gained	5/10		NM_001102416.3		P01042-1
HRG-AS1	ENST00000630178.2 linkuse as main transcript	n.136-8689G>A		intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251400

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135872

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 SAS exome

AF:

0.0000327

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

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000688

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

High molecular weight kininogen deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 04, 2023

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. -

Kininogen deficiency, total

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 05, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Benign

-0.11

Cadd

Pathogenic

Dann

Benign

0.96

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.015

MutationTaster

Benign

1.0

A;A;A

Vest4

0.79, 0.76

GERP RS

-4.8

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over