rs710446

Positions:

• chr3-186742138-T-C
• chr3-186742138-T-G

Variant summary

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

The NM_001102416.3(KNG1):​c.1742T>C​(p.Ile581Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 1,613,454 control chromosomes in the GnomAD database, including 138,838 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 0.44 (14830 hom., cov: 31)
  • Exomes 𝑓: 0.41 (124008 hom.)
• 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:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2191133E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNG1	NM_001102416.3	c.1742T>C	p.Ile581Thr	missense_variant	10/10	ENST00000644859.2	NP_001095886.1
KNG1	NM_000893.4	c.1203+539T>C		intron_variant			NP_000884.1
KNG1	NM_001166451.2	c.1095+539T>C		intron_variant			NP_001159923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2	c.1742T>C	p.Ile581Thr	missense_variant	10/10		NM_001102416.3	ENSP00000493985.1

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66362 AN: 151694 Hom.: 14812 Cov.: 31

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.516

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.449

GnomAD3 exomes AF: 0.416 AC: 103851 AN: 249494 Hom.: 21948 AF XY: 0.413 AC XY: 55963 AN XY: 135354

Gnomad AFR exome AF: 0.518

Gnomad AMR exome AF: 0.469

Gnomad ASJ exome AF: 0.515

Gnomad EAS exome AF: 0.309

Gnomad SAS exome AF: 0.376

Gnomad FIN exome AF: 0.373

Gnomad NFE exome AF: 0.413

Gnomad OTH exome AF: 0.432

GnomAD4 exome AF: 0.410 AC: 599182 AN: 1461642 Hom.: 124008 Cov.: 46 AF XY: 0.409 AC XY: 297535 AN XY: 727134

Gnomad4 AFR exome AF: 0.526

Gnomad4 AMR exome AF: 0.467

Gnomad4 ASJ exome AF: 0.517

Gnomad4 EAS exome AF: 0.295

Gnomad4 SAS exome AF: 0.381

Gnomad4 FIN exome AF: 0.375

Gnomad4 NFE exome AF: 0.409

Gnomad4 OTH exome AF: 0.421

GnomAD4 genome AF: 0.438 AC: 66431 AN: 151812 Hom.: 14830 Cov.: 31 AF XY: 0.435 AC XY: 32251 AN XY: 74210

Gnomad4 AFR AF: 0.517

Gnomad4 AMR AF: 0.449

Gnomad4 ASJ AF: 0.516

Gnomad4 EAS AF: 0.294

Gnomad4 SAS AF: 0.360

Gnomad4 FIN AF: 0.367

Gnomad4 NFE AF: 0.412

Gnomad4 OTH AF: 0.445

Alfa AF: 0.420 Hom.: 33299

Bravo AF: 0.450

TwinsUK AF: 0.416 AC: 1541

ALSPAC AF: 0.392 AC: 1511

ESP6500AA AF: 0.501 AC: 1968

ESP6500EA AF: 0.414 AC: 3422

ExAC AF: 0.415 AC: 50192

Asia WGS AF: 0.357 AC: 1242 AN: 3478

EpiCase AF: 0.418

EpiControl AF: 0.424

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.8
DANN	Benign	0.54
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.22	.;T
MetaRNN	Benign	0.00012	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.2	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	1.7	N;.
REVEL	Benign	0.093
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.0	B;B
Vest4		0.029
MPC		0.077
ClinPred		0.014	T
GERP RS		5.6
Varity_R		0.023
gMVP		0.082

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: rs710446; hg19: chr3-186459927; COSMIC: COSV53975922; COSMIC: COSV53975922;