chr3-186743302-G-A

Position:

• chr3-186743302-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001102416.3(KNG1):​c.*971G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 182,734 control chromosomes in the GnomAD database, including 5,538 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 0.25 (4733 hom., cov: 33)
  • Exomes 𝑓: 0.22 (805 hom.)
• Consequence: KNG1 NM_001102416.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.933

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KNG1	NM_001102416.3	c.*971G>A		3_prime_UTR_variant	10/10	ENST00000644859.2
KNG1	NM_000893.4	c.1204-403G>A		intron_variant
KNG1	NM_001166451.2	c.1096-403G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNG1	ENST00000644859.2	c.*971G>A		3_prime_UTR_variant	10/10		NM_001102416.3
HRG-AS1	ENST00000630178.2	n.135+401C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37662 AN: 151986 Hom.: 4728 Cov.: 33

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.224

GnomAD4 exome AF: 0.218 AC: 6664 AN: 30630 Hom.: 805 Cov.: 0 AF XY: 0.219 AC XY: 3496 AN XY: 15976

Gnomad4 AFR exome AF: 0.260

Gnomad4 AMR exome AF: 0.243

Gnomad4 ASJ exome AF: 0.149

Gnomad4 EAS exome AF: 0.136

Gnomad4 SAS exome AF: 0.190

Gnomad4 FIN exome AF: 0.258

Gnomad4 NFE exome AF: 0.226

Gnomad4 OTH exome AF: 0.226

GnomAD4 genome AF: 0.248 AC: 37675 AN: 152104 Hom.: 4733 Cov.: 33 AF XY: 0.245 AC XY: 18232 AN XY: 74366

Gnomad4 AFR AF: 0.287

Gnomad4 AMR AF: 0.230

Gnomad4 ASJ AF: 0.186

Gnomad4 EAS AF: 0.145

Gnomad4 SAS AF: 0.189

Gnomad4 FIN AF: 0.280

Gnomad4 NFE AF: 0.238

Gnomad4 OTH AF: 0.224

Alfa AF: 0.263 Hom.: 884

Bravo AF: 0.248

Asia WGS AF: 0.186 AC: 646 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.9
DANN	Benign	0.42

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: rs5030093; hg19: chr3-186461091;