chr3-186725229-T-C

Variant names:

• chr3-186725229-T-C
• rs1656922
• NM_001102416.3:c.533T>C

Variant summary

Our verdict is Benign. The variant received -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. 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.

• 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
• Publications: 43 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
KNG1	NM_001102416.3	c.533T>C	p.Met178Thr	missense_variant	Exon 4 of 10	ENST00000644859.2	NP_001095886.1
KNG1	NM_000893.4	c.533T>C	p.Met178Thr	missense_variant	Exon 4 of 11		NP_000884.1
KNG1	NM_001166451.2	c.533T>C	p.Met178Thr	missense_variant	Exon 4 of 10		NP_001159923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2	c.533T>C	p.Met178Thr	missense_variant	Exon 4 of 10		NM_001102416.3	ENSP00000493985.1

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

GnomAD2 exomes AF: 0.537 AC: 135013 AN: 251444 AF XY: 0.533

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 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

African (AFR) AF: 0.590 AC: 19733 AN: 33474

American (AMR) AF: 0.648 AC: 28968 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.525 AC: 13711 AN: 26132

East Asian (EAS) AF: 0.338 AC: 13404 AN: 39692

South Asian (SAS) AF: 0.520 AC: 44812 AN: 86248

European-Finnish (FIN) AF: 0.522 AC: 27885 AN: 53408

Middle Eastern (MID) AF: 0.590 AC: 3401 AN: 5768

European-Non Finnish (NFE) AF: 0.517 AC: 574337 AN: 1111348

Other (OTH) AF: 0.525 AC: 31703 AN: 60376

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

African (AFR) AF: 0.588 AC: 24369 AN: 41410

American (AMR) AF: 0.569 AC: 8688 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1852 AN: 3470

East Asian (EAS) AF: 0.367 AC: 1896 AN: 5166

South Asian (SAS) AF: 0.507 AC: 2439 AN: 4810

European-Finnish (FIN) AF: 0.523 AC: 5527 AN: 10560

Middle Eastern (MID) AF: 0.623 AC: 182 AN: 292

European-Non Finnish (NFE) AF: 0.522 AC: 35511 AN: 67972

Other (OTH) AF: 0.545 AC: 1148 AN: 2108

Alfa AF: 0.532 Hom.: 82714

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
DEOGEN2	Benign	0.19	.;T;.;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0041	N
LIST_S2	Benign	0.027	.;.;T;T;T
MetaRNN	Benign	0.0000071	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.67	N;N;N;N;N
PhyloP100		-0.044
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.4	.;N;N;N;.
REVEL	Benign	0.012
Sift	Benign	0.75	.;T;T;T;.
Sift4G	Benign	0.68	.;T;T;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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1656922; hg19: chr3-186443018; COSMIC: COSV53976735; COSMIC: COSV53976735;