rs1621816

chr3-186721384-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.307-1053T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 152,142 control chromosomes in the GnomAD database, including 8,188 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 0.32 (8183 hom., cov: 32)
  • Exomes 𝑓: 0.33 (5 hom.)
• Consequence: KNG1 NM_001102416.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.53

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=-0.99).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KNG1	NM_001102416.3	c.307-1053T>C		intron_variant		ENST00000644859.2
KNG1	NM_000893.4	c.307-1053T>C		intron_variant
KNG1	NM_001166451.2	c.307-1053T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNG1	ENST00000644859.2	c.307-1053T>C		intron_variant			NM_001102416.3
HRG-AS1	ENST00000630178.2	n.136-2815A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.319 AC: 48440 AN: 151930 Hom.: 8182 Cov.: 32

Gnomad AFR AF: 0.406

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.313

GnomAD4 exome AF: 0.330 AC: 31 AN: 94 Hom.: 5 Cov.: 0 AF XY: 0.338 AC XY: 23 AN XY: 68

Gnomad4 AFR exome AF: 1.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.200

Gnomad4 NFE exome AF: 0.343

Gnomad4 OTH exome AF: 0.333

GnomAD4 genome AF: 0.319 AC: 48471 AN: 152048 Hom.: 8183 Cov.: 32 AF XY: 0.318 AC XY: 23603 AN XY: 74310

Gnomad4 AFR AF: 0.406

Gnomad4 AMR AF: 0.238

Gnomad4 ASJ AF: 0.281

Gnomad4 EAS AF: 0.360

Gnomad4 SAS AF: 0.480

Gnomad4 FIN AF: 0.251

Gnomad4 NFE AF: 0.282

Gnomad4 OTH AF: 0.311

Alfa AF: 0.297 Hom.: 5023

Bravo AF: 0.317

Asia WGS AF: 0.416 AC: 1446 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
Cadd	Benign	0.13
Dann	Benign	0.73

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: rs1621816; hg19: chr3-186439173;