3-186727258-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 10P and 4B. PVS1PP5_ModerateBS2
The NM_001102416.3(KNG1):c.586C>T(p.Arg196Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,612,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001102416.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KNG1 | NM_001102416.3 | c.586C>T | p.Arg196Ter | stop_gained | 5/10 | ENST00000644859.2 | NP_001095886.1 | |
KNG1 | NM_000893.4 | c.586C>T | p.Arg196Ter | stop_gained | 5/11 | NP_000884.1 | ||
KNG1 | NM_001166451.2 | c.564+1998C>T | intron_variant | NP_001159923.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KNG1 | ENST00000644859.2 | c.586C>T | p.Arg196Ter | stop_gained | 5/10 | NM_001102416.3 | ENSP00000493985 | |||
HRG-AS1 | ENST00000630178.2 | n.136-8689G>A | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152126Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251400Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135872
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1460772Hom.: 0 Cov.: 29 AF XY: 0.0000151 AC XY: 11AN XY: 726800
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74310
ClinVar
Submissions by phenotype
High molecular weight kininogen deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz | Sep 04, 2023 | We identified this variant, NM_001102416.3(KNG1):c.586C>T (p.Arg196*) in homozygosity as the cause of high-molecular-weight kininogen deficiency in an individual (<1% HK activity, prolonged aPTT) (PMID: 36700498). Large deletions were excluded via ddPCR. The case was originally described by Nazir et al (DOI: 10.15406/htij.2019.07.00197). The c.586C>T variant is the first and most frequently reported HK deficiency-causing variant in the literature. It has been described in three unrelated homozygous literature cases: it was first identified by Cheung et al. (PMID: 7901207) and also described by Ishimaru et al. (PMID. 10071463) and Nakamura et al. (PMID: 3853954). All three literature cases have barely measurable HK levels (<1% HK activity and antigen) and also very low to barely detectable levels of low-molecular-weight kininogen (LK), thus this variant results in combined HK and LK deficiency. The MAF of this variant is 0.001-0.007% (dbSNP). Therefore, we classified this variant as pathogenic. - |
Kininogen deficiency, total Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 05, 1993 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at