rs2062632

Positions:

• chr3-186743392-T-C

Variant summary

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

The NM_001102416.3(KNG1):​c.*1061T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 322,296 control chromosomes in the GnomAD database, including 6,737 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 0.19 (2969 hom., cov: 33)
  • Exomes 𝑓: 0.20 (3768 hom.)
• Consequence: KNG1 NM_001102416.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0300

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=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNG1	NM_001102416.3	c.*1061T>C		3_prime_UTR_variant	10/10	ENST00000644859.2	NP_001095886.1
KNG1	NM_000893.4	c.1204-313T>C		intron_variant			NP_000884.1
KNG1	NM_001166451.2	c.1096-313T>C		intron_variant			NP_001159923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2	c.*1061T>C		3_prime_UTR_variant	10/10		NM_001102416.3	ENSP00000493985.1

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28961 AN: 152068 Hom.: 2970 Cov.: 33

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.186

GnomAD4 exome AF: 0.203 AC: 34469 AN: 170110 Hom.: 3768 Cov.: 0 AF XY: 0.202 AC XY: 18127 AN XY: 89772

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.206

Gnomad4 ASJ exome AF: 0.182

Gnomad4 EAS exome AF: 0.133

Gnomad4 SAS exome AF: 0.196

Gnomad4 FIN exome AF: 0.235

Gnomad4 NFE exome AF: 0.213

Gnomad4 OTH exome AF: 0.208

GnomAD4 genome AF: 0.190 AC: 28961 AN: 152186 Hom.: 2969 Cov.: 33 AF XY: 0.190 AC XY: 14160 AN XY: 74408

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.200

Gnomad4 ASJ AF: 0.196

Gnomad4 EAS AF: 0.149

Gnomad4 SAS AF: 0.206

Gnomad4 FIN AF: 0.245

Gnomad4 NFE AF: 0.222

Gnomad4 OTH AF: 0.187

Alfa AF: 0.217 Hom.: 4884

Bravo AF: 0.185

Asia WGS AF: 0.183 AC: 637 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.0
DANN	Benign	0.86

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: rs2062632; hg19: chr3-186461181;