rs698078

chr3-186741438-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.1126-84A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 1,236,656 control chromosomes in the GnomAD database, including 104,173 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 0.43 (14689 hom., cov: 33)
  • Exomes 𝑓: 0.40 (89484 hom.)
• Consequence: KNG1 NM_001102416.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0820

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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KNG1	NM_001102416.3	c.1126-84A>G		intron_variant		ENST00000644859.2
KNG1	NM_000893.4	c.1126-84A>G		intron_variant
KNG1	NM_001166451.2	c.1018-84A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNG1	ENST00000644859.2	c.1126-84A>G		intron_variant			NM_001102416.3
HRG-AS1	ENST00000630178.2	n.135+2265T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.435 AC: 66046 AN: 151984 Hom.: 14670 Cov.: 33

Gnomad AFR AF: 0.516

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.513

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.356

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.443

GnomAD4 exome AF: 0.403 AC: 437485 AN: 1084554 Hom.: 89484 AF XY: 0.403 AC XY: 220694 AN XY: 547686

Gnomad4 AFR exome AF: 0.523

Gnomad4 AMR exome AF: 0.467

Gnomad4 ASJ exome AF: 0.513

Gnomad4 EAS exome AF: 0.286

Gnomad4 SAS exome AF: 0.375

Gnomad4 FIN exome AF: 0.376

Gnomad4 NFE exome AF: 0.403

Gnomad4 OTH exome AF: 0.415

GnomAD4 genome AF: 0.435 AC: 66116 AN: 152102 Hom.: 14689 Cov.: 33 AF XY: 0.432 AC XY: 32114 AN XY: 74344

Gnomad4 AFR AF: 0.516

Gnomad4 AMR AF: 0.446

Gnomad4 ASJ AF: 0.513

Gnomad4 EAS AF: 0.290

Gnomad4 SAS AF: 0.357

Gnomad4 FIN AF: 0.367

Gnomad4 NFE AF: 0.408

Gnomad4 OTH AF: 0.439

Alfa AF: 0.427 Hom.: 3382

Bravo AF: 0.447

Asia WGS AF: 0.354 AC: 1233 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	4.7
Dann	Benign	0.53

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: rs698078; hg19: chr3-186459227; COSMIC: COSV53979388; COSMIC: COSV53979388;