rs5030094

chr3-186743369-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001102416.3(KNG1):c.*1038T>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 0.0154 in 275,784 control chromosomes in the GnomAD database, including 43 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 0.016 (27 hom., cov: 33)
  • Exomes 𝑓: 0.015 (16 hom.)
• Consequence: KNG1 NM_001102416.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.02

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=-0.86).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.016 (2444/152354) while in subpopulation NFE AF= 0.0191 (1301/68028). AF 95% confidence interval is 0.0183. There are 27 homozygotes in gnomad4. There are 1101 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2438 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KNG1	NM_001102416.3	c.*1038T>C		3_prime_UTR_variant	10/10	ENST00000644859.2
KNG1	NM_000893.4	c.1204-336T>C		intron_variant
KNG1	NM_001166451.2	c.1096-336T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNG1	ENST00000644859.2	c.*1038T>C		3_prime_UTR_variant	10/10		NM_001102416.3
HRG-AS1	ENST00000630178.2	n.135+334A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2438 AN: 152236 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00846

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0191

Gnomad OTH AF: 0.0167

GnomAD4 exome AF: 0.0146 AC: 1796 AN: 123430 Hom.: 16 Cov.: 0 AF XY: 0.0134 AC XY: 875 AN XY: 65170

Gnomad4 AFR exome AF: 0.0133

Gnomad4 AMR exome AF: 0.0134

Gnomad4 ASJ exome AF: 0.0143

Gnomad4 EAS exome AF: 0.0105

Gnomad4 SAS exome AF: 0.00470

Gnomad4 FIN exome AF: 0.00439

Gnomad4 NFE exome AF: 0.0178

Gnomad4 OTH exome AF: 0.0170

GnomAD4 genome AF: 0.0160 AC: 2444 AN: 152354 Hom.: 27 Cov.: 33 AF XY: 0.0148 AC XY: 1101 AN XY: 74498

Gnomad4 AFR AF: 0.0158

Gnomad4 AMR AF: 0.0164

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00828

Gnomad4 SAS AF: 0.00662

Gnomad4 FIN AF: 0.00442

Gnomad4 NFE AF: 0.0191

Gnomad4 OTH AF: 0.0198

Alfa AF: 0.0187 Hom.: 25

Bravo AF: 0.0167

Asia WGS AF: 0.0200 AC: 68 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.14
Dann	Benign	0.67

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: rs5030094; hg19: chr3-186461158;