rs559129841

Positions:

• chr3-186742258-CAGTT-C
• chr3-186742258-CAGTT-CAGTTAGTT

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PVS1_Moderate BS2

The NM_001102416.3(KNG1):​c.1866_1869del​(p.Ser623LysfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 1,614,162 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: KNG1 NM_001102416.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48

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 Likely_benign. Variant got -2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0372 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS2: High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KNG1	NM_001102416.3	c.1866_1869del	p.Ser623LysfsTer8	frameshift_variant	10/10	ENST00000644859.2
KNG1	NM_000893.4	c.1203+663_1203+666del		intron_variant
KNG1	NM_001166451.2	c.1095+663_1095+666del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNG1	ENST00000644859.2	c.1866_1869del	p.Ser623LysfsTer8	frameshift_variant	10/10		NM_001102416.3
HRG-AS1	ENST00000630178.2	n.135+1441_135+1444del		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00557

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000369 AC: 92 AN: 249414 Hom.: 0 AF XY: 0.000377 AC XY: 51 AN XY: 135296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00417

Gnomad SAS exome AF: 0.000458

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000159 AC: 232 AN: 1461868 Hom.: 0 AF XY: 0.000176 AC XY: 128 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00390

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74468

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00578

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000116 Hom.: 0

Bravo AF: 0.000280

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

High molecular weight kininogen deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

reference population

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Mar 18, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs559129841; hg19: chr3-186460047;