chr3-186718609-A-G

Position:

• chr3-186718609-A-G

Variant summary

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

The NM_001102416.3(KNG1):​c.195+872A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 150,892 control chromosomes in the GnomAD database, including 9,276 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 0.34 (9262 hom., cov: 27)
  • Exomes 𝑓: 0.37 (14 hom.)
• Consequence: KNG1 NM_001102416.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.539

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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) 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.195+872A>G		intron_variant		ENST00000644859.2	NP_001095886.1
KNG1	NM_000893.4	c.195+872A>G		intron_variant			NP_000884.1
KNG1	NM_001166451.2	c.195+872A>G		intron_variant			NP_001159923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2	c.195+872A>G		intron_variant			NM_001102416.3	ENSP00000493985.1

Frequencies

GnomAD3 genomes AF: 0.345 AC: 51922 AN: 150576 Hom.: 9259 Cov.: 27

Gnomad AFR AF: 0.413

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.275

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.433

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.316

GnomAD4 exome AF: 0.372 AC: 73 AN: 196 Hom.: 14 Cov.: 0 AF XY: 0.351 AC XY: 40 AN XY: 114

Gnomad4 AFR exome AF: 0.667

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.360

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.345 AC: 51963 AN: 150696 Hom.: 9262 Cov.: 27 AF XY: 0.342 AC XY: 25154 AN XY: 73498

Gnomad4 AFR AF: 0.413

Gnomad4 AMR AF: 0.284

Gnomad4 ASJ AF: 0.275

Gnomad4 EAS AF: 0.323

Gnomad4 SAS AF: 0.433

Gnomad4 FIN AF: 0.308

Gnomad4 NFE AF: 0.322

Gnomad4 OTH AF: 0.316

Alfa AF: 0.314 Hom.: 8619

Bravo AF: 0.342

Asia WGS AF: 0.389 AC: 1350 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	8.6
DANN	Benign	0.70

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: rs1851665; hg19: chr3-186436398;