rs1656922

chr3-186725229-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001102416.3(KNG1):c.533T>C(p.Met178Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,613,118 control chromosomes in the GnomAD database, including 220,800 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.54 (22332 hom., cov: 31)
  • Exomes 𝑓: 0.52 (198468 hom.)
• Consequence: KNG1 NM_001102416.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0440

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.1061336E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.582 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KNG1	NM_001102416.3	c.533T>C	p.Met178Thr	missense_variant	4/10	ENST00000644859.2
KNG1	NM_000893.4	c.533T>C	p.Met178Thr	missense_variant	4/11
KNG1	NM_001166451.2	c.533T>C	p.Met178Thr	missense_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNG1	ENST00000644859.2	c.533T>C	p.Met178Thr	missense_variant	4/10		NM_001102416.3
HRG-AS1	ENST00000630178.2	n.136-6660A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.540 AC: 81960 AN: 151836 Hom.: 22314 Cov.: 31

Gnomad AFR AF: 0.588

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.507

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.618

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.547

GnomAD3 exomes AF: 0.537 AC: 135013 AN: 251444 Hom.: 36947 AF XY: 0.533 AC XY: 72398 AN XY: 135900

Gnomad AFR exome AF: 0.593

Gnomad AMR exome AF: 0.654

Gnomad ASJ exome AF: 0.527

Gnomad EAS exome AF: 0.377

Gnomad SAS exome AF: 0.517

Gnomad FIN exome AF: 0.522

Gnomad NFE exome AF: 0.528

Gnomad OTH exome AF: 0.545

GnomAD4 exome AF: 0.519 AC: 757954 AN: 1461164 Hom.: 198468 Cov.: 44 AF XY: 0.519 AC XY: 376984 AN XY: 726924

Gnomad4 AFR exome AF: 0.590

Gnomad4 AMR exome AF: 0.648

Gnomad4 ASJ exome AF: 0.525

Gnomad4 EAS exome AF: 0.338

Gnomad4 SAS exome AF: 0.520

Gnomad4 FIN exome AF: 0.522

Gnomad4 NFE exome AF: 0.517

Gnomad4 OTH exome AF: 0.525

GnomAD4 genome AF: 0.540 AC: 82034 AN: 151954 Hom.: 22332 Cov.: 31 AF XY: 0.539 AC XY: 40039 AN XY: 74282

Gnomad4 AFR AF: 0.588

Gnomad4 AMR AF: 0.569

Gnomad4 ASJ AF: 0.534

Gnomad4 EAS AF: 0.367

Gnomad4 SAS AF: 0.507

Gnomad4 FIN AF: 0.523

Gnomad4 NFE AF: 0.522

Gnomad4 OTH AF: 0.545

Alfa AF: 0.527 Hom.: 54203

Bravo AF: 0.548

ESP6500AA AF: 0.596 AC: 2628

ESP6500EA AF: 0.520 AC: 4470

ExAC AF: 0.537 AC: 65219

Asia WGS AF: 0.468 AC: 1630 AN: 3478

EpiCase AF: 0.528

EpiControl AF: 0.530

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.0
Dann	Benign	0.47
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0041	N
MetaRNN	Benign	0.0000071	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.67	N;N;N;N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.26	T
Polyphen		0.0	B;B;.;B;B
Vest4		0.014, 0.058, 0.048
MPC		0.070
ClinPred		0.0032	T
GERP RS		-0.39
Varity_R		0.060
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1656922; hg19: chr3-186443018; COSMIC: COSV53976735; COSMIC: COSV53976735;