rs5030062

Positions:

• chr3-186736391-A-C

Variant summary

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

The NM_001102416.3(KNG1):​c.931-2708A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 152,040 control chromosomes in the GnomAD database, including 9,649 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 0.35 (9649 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: KNG1 NM_001102416.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.375

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=-0.8).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNG1	NM_001102416.3	c.931-2708A>C		intron_variant		ENST00000644859.2	NP_001095886.1
KNG1	NM_000893.4	c.931-2708A>C		intron_variant			NP_000884.1
KNG1	NM_001166451.2	c.823-2708A>C		intron_variant			NP_001159923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2	c.931-2708A>C		intron_variant			NM_001102416.3	ENSP00000493985.1

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53710 AN: 151922 Hom.: 9638 Cov.: 33

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.387

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.372

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.354 AC: 53753 AN: 152040 Hom.: 9649 Cov.: 33 AF XY: 0.352 AC XY: 26181 AN XY: 74278

Gnomad4 AFR AF: 0.309

Gnomad4 AMR AF: 0.388

Gnomad4 ASJ AF: 0.459

Gnomad4 EAS AF: 0.281

Gnomad4 SAS AF: 0.338

Gnomad4 FIN AF: 0.334

Gnomad4 NFE AF: 0.378

Gnomad4 OTH AF: 0.368

Alfa AF: 0.379 Hom.: 22629

Bravo AF: 0.358

Asia WGS AF: 0.322 AC: 1118 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.8
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: rs5030062; hg19: chr3-186454180;