rs1624230

Positions:

• chr3-186721146-C-A
• chr3-186721146-C-T

Variant summary

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

The NM_001102416.3(KNG1):​c.306+931C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 151,800 control chromosomes in the GnomAD database, including 13,955 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 0.42 (13955 hom., cov: 31)
  • Exomes 𝑓: 0.30 (0 hom.)
• Consequence: KNG1 NM_001102416.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.28

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 (SAS) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNG1	NM_001102416.3	c.306+931C>A		intron_variant		ENST00000644859.2	NP_001095886.1
KNG1	NM_000893.4	c.306+931C>A		intron_variant			NP_000884.1
KNG1	NM_001166451.2	c.306+931C>A		intron_variant			NP_001159923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2	c.306+931C>A		intron_variant			NM_001102416.3	ENSP00000493985.1

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64155 AN: 151672 Hom.: 13949 Cov.: 31

Gnomad AFR AF: 0.484

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.612

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.401

GnomAD4 exome AF: 0.300 AC: 3 AN: 10 Hom.: 0 AF XY: 0.333 AC XY: 2 AN XY: 6

Gnomad4 AFR exome AF: 0.00

Gnomad4 NFE exome AF: 0.375

GnomAD4 genome AF: 0.423 AC: 64198 AN: 151790 Hom.: 13955 Cov.: 31 AF XY: 0.422 AC XY: 31342 AN XY: 74216

Gnomad4 AFR AF: 0.484

Gnomad4 AMR AF: 0.357

Gnomad4 ASJ AF: 0.365

Gnomad4 EAS AF: 0.410

Gnomad4 SAS AF: 0.610

Gnomad4 FIN AF: 0.385

Gnomad4 NFE AF: 0.396

Gnomad4 OTH AF: 0.400

Alfa AF: 0.392 Hom.: 19920

Bravo AF: 0.417

Asia WGS AF: 0.509 AC: 1769 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	1.3
DANN	Benign	0.72

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: rs1624230; hg19: chr3-186438935;