3-186727263-T-G

Position:

• chr3-186727263-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001102416.3(KNG1):​c.591T>G​(p.Ile197Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,610,870 control chromosomes in the GnomAD database, including 11,734 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.095 (850 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10884 hom.)
• Consequence: KNG1 NM_001102416.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.48

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]

HRG-AS1 (HGNC:55915): (HRG and FETUB antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006281644).
• BP6: Variant 3-186727263-T-G is Benign according to our data. Variant chr3-186727263-T-G is described in ClinVar as [Benign]. Clinvar id is 3038288.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KNG1	NM_001102416.3	c.591T>G	p.Ile197Met	missense_variant	5/10	ENST00000644859.2
KNG1	NM_000893.4	c.591T>G	p.Ile197Met	missense_variant	5/11
KNG1	NM_001166451.2	c.564+2003T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNG1	ENST00000644859.2	c.591T>G	p.Ile197Met	missense_variant	5/10		NM_001102416.3
HRG-AS1	ENST00000630178.2	n.136-8694A>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0954 AC: 14520 AN: 152160 Hom.: 851 Cov.: 32

Gnomad AFR AF: 0.0394

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.0809

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.104

GnomAD3 exomes AF: 0.119 AC: 29955 AN: 251386 Hom.: 2185 AF XY: 0.126 AC XY: 17124 AN XY: 135864

Gnomad AFR exome AF: 0.0365

Gnomad AMR exome AF: 0.0662

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.167

Gnomad SAS exome AF: 0.221

Gnomad FIN exome AF: 0.132

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.116 AC: 168737 AN: 1458592 Hom.: 10884 Cov.: 30 AF XY: 0.119 AC XY: 86534 AN XY: 725894

Gnomad4 AFR exome AF: 0.0353

Gnomad4 AMR exome AF: 0.0682

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.156

Gnomad4 SAS exome AF: 0.217

Gnomad4 FIN exome AF: 0.130

Gnomad4 NFE exome AF: 0.110

Gnomad4 OTH exome AF: 0.115

GnomAD4 genome AF: 0.0953 AC: 14516 AN: 152278 Hom.: 850 Cov.: 32 AF XY: 0.0983 AC XY: 7320 AN XY: 74450

Gnomad4 AFR AF: 0.0393

Gnomad4 AMR AF: 0.0808

Gnomad4 ASJ AF: 0.110

Gnomad4 EAS AF: 0.169

Gnomad4 SAS AF: 0.230

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.104

Alfa AF: 0.109 Hom.: 1884

Bravo AF: 0.0861

TwinsUK AF: 0.114 AC: 423

ALSPAC AF: 0.112 AC: 431

ESP6500AA AF: 0.0406 AC: 179

ESP6500EA AF: 0.115 AC: 986

ExAC AF: 0.120 AC: 14632

Asia WGS AF: 0.185 AC: 640 AN: 3478

EpiCase AF: 0.106

EpiControl AF: 0.107

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

KNG1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.1
DANN	Benign	0.97
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.019	N
MetaRNN	Benign	0.0063	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M;M;M;M
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.44	T
Polyphen		0.97	D;P;D;P
Vest4		0.16, 0.35
MPC		0.21
ClinPred		0.042	T
GERP RS		-10
Varity_R		0.13
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs2304456; hg19: chr3-186445052; COSMIC: COSV53978225; COSMIC: COSV53978225;