3-186740984-TTGTTGTTGTTGTTGTTTGTTTTTTGT-GGTGGTGGTGGTGGTGGTTTGTTTTTGG

Variant names:

• chr3-186740984-TTGTTGTTGTTGTTGTTTGTTTTTTGT-GGTGGTGGTGGTGGTGGTTTGTTTTTGG
• rs869320718
• NM_001102416.3:c.1126-538_1126-512delTTGTTGTTGTTGTTGTTTGTTTTTTGTinsGGTGGTGGTGGTGGTGGTTTGTTTTTGG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001102416.3(KNG1):​c.1126-538_1126-512delTTGTTGTTGTTGTTGTTTGTTTTTTGTinsGGTGGTGGTGGTGGTGGTTTGTTTTTGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Affects (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: KNG1 NM_001102416.3 intron
• Clinical Significance: Affects no assertion criteria provided O:1
• Conservation: PhyloP100: 0.226
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001102416.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNG1	NM_001102416.3	MANE Select	c.1126-538_1126-512delTTGTTGTTGTTGTTGTTTGTTTTTTGTinsGGTGGTGGTGGTGGTGGTTTGTTTTTGG		intron	N/A	NP_001095886.1
	KNG1	NM_000893.4		c.1126-538_1126-512delTTGTTGTTGTTGTTGTTTGTTTTTTGTinsGGTGGTGGTGGTGGTGGTTTGTTTTTGG		intron	N/A	NP_000884.1
	KNG1	NM_001166451.2		c.1018-538_1018-512delTTGTTGTTGTTGTTGTTTGTTTTTTGTinsGGTGGTGGTGGTGGTGGTTTGTTTTTGG		intron	N/A	NP_001159923.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNG1	ENST00000644859.2	MANE Select	c.1126-538_1126-512delTTGTTGTTGTTGTTGTTTGTTTTTTGTinsGGTGGTGGTGGTGGTGGTTTGTTTTTGG		intron	N/A	ENSP00000493985.1
	KNG1	ENST00000287611.8	TSL:1	c.1126-538_1126-512delTTGTTGTTGTTGTTGTTTGTTTTTTGTinsGGTGGTGGTGGTGGTGGTTTGTTTTTGG		intron	N/A	ENSP00000287611.2
	KNG1	ENST00000447445.1	TSL:3	c.1018-538_1018-512delTTGTTGTTGTTGTTGTTTGTTTTTTGTinsGGTGGTGGTGGTGGTGGTTTGTTTTTGG		intron	N/A	ENSP00000396025.1

Frequencies

GnomAD3 genomes Cov.: 30

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 30

ClinVar

Significance: Affects

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

High molecular weight kininogen deficiency Other:1

Jun 01, 2003

OMIM

Significance: Affects

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.23

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs869320718; hg19: chr3-186458773;