3-186743735-C-T

Position:

• chr3-186743735-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PVS1_Moderate BA1

The NM_000893.4(KNG1):​c.1234C>T​(p.Arg412*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0302 in 1,613,294 control chromosomes in the GnomAD database, including 1,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (53 hom., cov: 33)
  • Exomes 𝑓: 0.031 (963 hom.)
• Consequence: KNG1 NM_000893.4 stop_gained
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.776

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:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0389 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNG1	NM_001102416.3	c.*1404C>T		3_prime_UTR_variant	10/10	ENST00000644859.2	NP_001095886.1
KNG1	NM_000893.4	c.1234C>T	p.Arg412*	stop_gained	11/11		NP_000884.1
KNG1	NM_001166451.2	c.1126C>T	p.Arg376*	stop_gained	10/10		NP_001159923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2	c.*1404C>T		3_prime_UTR_variant	10/10		NM_001102416.3	ENSP00000493985.1

Frequencies

GnomAD3 genomes AF: 0.0199 AC: 3020 AN: 152138 Hom.: 53 Cov.: 33

Gnomad AFR AF: 0.00599

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.00770

Gnomad SAS AF: 0.0743

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.0272

Gnomad OTH AF: 0.0215

GnomAD3 exomes AF: 0.0292 AC: 7325 AN: 250976 Hom.: 197 AF XY: 0.0335 AC XY: 4540 AN XY: 135670

Gnomad AFR exome AF: 0.00468

Gnomad AMR exome AF: 0.00613

Gnomad ASJ exome AF: 0.0416

Gnomad EAS exome AF: 0.00995

Gnomad SAS exome AF: 0.0830

Gnomad FIN exome AF: 0.0136

Gnomad NFE exome AF: 0.0303

Gnomad OTH exome AF: 0.0278

GnomAD4 exome AF: 0.0313 AC: 45681 AN: 1461038 Hom.: 963 Cov.: 30 AF XY: 0.0331 AC XY: 24090 AN XY: 726860

Gnomad4 AFR exome AF: 0.00338

Gnomad4 AMR exome AF: 0.00678

Gnomad4 ASJ exome AF: 0.0432

Gnomad4 EAS exome AF: 0.00688

Gnomad4 SAS exome AF: 0.0830

Gnomad4 FIN exome AF: 0.0136

Gnomad4 NFE exome AF: 0.0304

Gnomad4 OTH exome AF: 0.0342

GnomAD4 genome AF: 0.0198 AC: 3021 AN: 152256 Hom.: 53 Cov.: 33 AF XY: 0.0203 AC XY: 1508 AN XY: 74442

Gnomad4 AFR AF: 0.00597

Gnomad4 AMR AF: 0.0144

Gnomad4 ASJ AF: 0.0395

Gnomad4 EAS AF: 0.00772

Gnomad4 SAS AF: 0.0746

Gnomad4 FIN AF: 0.0103

Gnomad4 NFE AF: 0.0272

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0260 Hom.: 105

Bravo AF: 0.0185

TwinsUK AF: 0.0307 AC: 114

ALSPAC AF: 0.0246 AC: 95

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.0274 AC: 236

ExAC AF: 0.0312 AC: 3786

Asia WGS AF: 0.0310 AC: 106 AN: 3478

EpiCase AF: 0.0280

EpiControl AF: 0.0276

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Uncertain	1.0
Eigen	Benign	-0.093
Eigen_PC	Benign	-0.042
FATHMM_MKL	Benign	0.15	N
Vest4		0.52, 0.46
GERP RS		4.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs76438938; hg19: chr3-186461524;