chr3-186742138-T-G

Position:

• chr3-186742138-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001102416.3(KNG1):​c.1742T>G​(p.Ile581Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I581T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KNG1 NM_001102416.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.63

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.097378254).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KNG1	NM_001102416.3	c.1742T>G	p.Ile581Arg	missense_variant	10/10	ENST00000644859.2
KNG1	NM_000893.4	c.1203+539T>G		intron_variant
KNG1	NM_001166451.2	c.1095+539T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNG1	ENST00000644859.2	c.1742T>G	p.Ile581Arg	missense_variant	10/10		NM_001102416.3
HRG-AS1	ENST00000630178.2	n.135+1565A>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.24	.;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.097	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.86	P;P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.25	N;.
REVEL	Benign	0.084
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.0030	D;.
Polyphen		0.0	B;B
Vest4		0.15
MutPred		0.21		Gain of solvent accessibility (P = 0.0367);Gain of solvent accessibility (P = 0.0367);
MVP		0.50
MPC		0.11
ClinPred		0.21	T
GERP RS		5.6
Varity_R		0.059
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs710446; hg19: chr3-186459927;