rs266760

Positions:

• chr3-186743427-G-A
• chr3-186743427-G-C

Variant summary

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

The NM_001102416.3(KNG1):​c.*1096G>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 0.256 in 437,306 control chromosomes in the GnomAD database, including 15,407 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 0.29 (7091 hom., cov: 33)
  • Exomes 𝑓: 0.24 (8316 hom.)
• Consequence: KNG1 NM_001102416.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.43

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNG1	NM_001102416.3	c.*1096G>A		3_prime_UTR_variant	10/10	ENST00000644859.2	NP_001095886.1
KNG1	NM_000893.4	c.1204-278G>A		intron_variant			NP_000884.1
KNG1	NM_001166451.2	c.1096-278G>A		intron_variant			NP_001159923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2	c.*1096G>A		3_prime_UTR_variant	10/10		NM_001102416.3	ENSP00000493985.1

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44345 AN: 151912 Hom.: 7082 Cov.: 33

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.245

Gnomad OTH AF: 0.273

GnomAD4 exome AF: 0.236 AC: 67427 AN: 285276 Hom.: 8316 Cov.: 0 AF XY: 0.233 AC XY: 35648 AN XY: 152714

Gnomad4 AFR exome AF: 0.425

Gnomad4 AMR exome AF: 0.250

Gnomad4 ASJ exome AF: 0.215

Gnomad4 EAS exome AF: 0.133

Gnomad4 SAS exome AF: 0.211

Gnomad4 FIN exome AF: 0.265

Gnomad4 NFE exome AF: 0.240

Gnomad4 OTH exome AF: 0.249

GnomAD4 genome AF: 0.292 AC: 44379 AN: 152030 Hom.: 7091 Cov.: 33 AF XY: 0.289 AC XY: 21465 AN XY: 74304

Gnomad4 AFR AF: 0.422

Gnomad4 AMR AF: 0.249

Gnomad4 ASJ AF: 0.223

Gnomad4 EAS AF: 0.149

Gnomad4 SAS AF: 0.210

Gnomad4 FIN AF: 0.277

Gnomad4 NFE AF: 0.245

Gnomad4 OTH AF: 0.274

Alfa AF: 0.202 Hom.: 564

Bravo AF: 0.296

Asia WGS AF: 0.207 AC: 719 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.41
DANN	Benign	0.62

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: rs266760; hg19: chr3-186461216;