rs559129841
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PVS1_ModerateBS2
The NM_001102416.3(KNG1):βc.1866_1869delβ(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 (β ).
Frequency
Genomes: π 0.00020 ( 0 hom., cov: 32)
Exomes π: 0.00016 ( 0 hom. )
Consequence
KNG1
NM_001102416.3 frameshift
NM_001102416.3 frameshift
Scores
Not classified
Clinical Significance
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
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: 30AN: 152176Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
30
AN:
152176
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000369 AC: 92AN: 249414Hom.: 0 AF XY: 0.000377 AC XY: 51AN XY: 135296
GnomAD3 exomes
AF:
AC:
92
AN:
249414
Hom.:
AF XY:
AC XY:
51
AN XY:
135296
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000159 AC: 232AN: 1461868Hom.: 0 AF XY: 0.000176 AC XY: 128AN XY: 727228
GnomAD4 exome
AF:
AC:
232
AN:
1461868
Hom.:
AF XY:
AC XY:
128
AN XY:
727228
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.000204 AC: 31AN: 152294Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17AN XY: 74468
GnomAD4 genome
?
AF:
AC:
31
AN:
152294
Hom.:
Cov.:
32
AF XY:
AC XY:
17
AN XY:
74468
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
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:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at