3-186742138-T-C

Variant names:

• chr3-186742138-T-C
• rs710446
• NM_001102416.3:c.1742T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000644859.2(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. 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. I581R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.44 (14830 hom., cov: 31)
  • Exomes 𝑓: 0.41 (124008 hom.)
• Consequence: KNG1 ENST00000644859.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.63
• Publications: 82 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=1.2191133E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000644859.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNG1	NM_001102416.3	MANE Select	c.1742T>C	p.Ile581Thr	missense	Exon 10 of 10	NP_001095886.1
	KNG1	NM_000893.4		c.1203+539T>C		intron	N/A	NP_000884.1
	KNG1	NM_001166451.2		c.1095+539T>C		intron	N/A	NP_001159923.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNG1	ENST00000644859.2	MANE Select	c.1742T>C	p.Ile581Thr	missense	Exon 10 of 10	ENSP00000493985.1
	KNG1	ENST00000287611.8	TSL:1	c.1203+539T>C		intron	N/A	ENSP00000287611.2
	HRG-AS1	ENST00000629734.1	TSL:5	n.247A>G		non_coding_transcript_exon	Exon 2 of 3

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

GnomAD2 exomes AF: 0.416 AC: 103851 AN: 249494 AF XY: 0.413

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 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

African (AFR) AF: 0.526 AC: 17615 AN: 33466

American (AMR) AF: 0.467 AC: 20900 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 13504 AN: 26134

East Asian (EAS) AF: 0.295 AC: 11694 AN: 39698

South Asian (SAS) AF: 0.381 AC: 32827 AN: 86252

European-Finnish (FIN) AF: 0.375 AC: 20020 AN: 53416

Middle Eastern (MID) AF: 0.428 AC: 2471 AN: 5768

European-Non Finnish (NFE) AF: 0.409 AC: 454747 AN: 1111800

Other (OTH) AF: 0.421 AC: 25404 AN: 60384

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

African (AFR) AF: 0.517 AC: 21388 AN: 41360

American (AMR) AF: 0.449 AC: 6836 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.516 AC: 1790 AN: 3468

East Asian (EAS) AF: 0.294 AC: 1517 AN: 5160

South Asian (SAS) AF: 0.360 AC: 1731 AN: 4808

European-Finnish (FIN) AF: 0.367 AC: 3868 AN: 10534

Middle Eastern (MID) AF: 0.497 AC: 145 AN: 292

European-Non Finnish (NFE) AF: 0.412 AC: 27985 AN: 67930

Other (OTH) AF: 0.445 AC: 939 AN: 2110

Alfa AF: 0.424 Hom.: 66029

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 v4.9

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
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
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.2	N
PhyloP100		2.6
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
Vest4		0.029
MPC		0.077
ClinPred		0.014	T
GERP RS		5.6
Varity_R		0.023
gMVP		0.082
Mutation Taster		=92/8	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: rs710446; hg19: chr3-186459927; COSMIC: COSV53975922; COSMIC: COSV53975922;