chr3-186730370-T-C

Variant names:

• chr3-186730370-T-C
• rs5030039
• NM_001102416.3:c.673-1175T>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.673-1175T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 151,718 control chromosomes in the GnomAD database, including 4,272 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4272 hom., cov: 30)
• Consequence: KNG1 NM_001102416.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0180
• Publications: 4 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 (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNG1	NM_001102416.3	c.673-1175T>C		intron_variant	Intron 5 of 9	ENST00000644859.2	NP_001095886.1
KNG1	NM_000893.4	c.673-1175T>C		intron_variant	Intron 5 of 10		NP_000884.1
KNG1	NM_001166451.2	c.565-1175T>C		intron_variant	Intron 4 of 9		NP_001159923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2	c.673-1175T>C		intron_variant	Intron 5 of 9		NM_001102416.3	ENSP00000493985.1

Frequencies

GnomAD3 genomes AF: 0.231 AC: 34959 AN: 151600 Hom.: 4277 Cov.: 30

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.249

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.230 AC: 34958 AN: 151718 Hom.: 4272 Cov.: 30 AF XY: 0.230 AC XY: 17041 AN XY: 74120

African (AFR) AF: 0.163 AC: 6748 AN: 41412

American (AMR) AF: 0.201 AC: 3052 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 884 AN: 3468

East Asian (EAS) AF: 0.277 AC: 1427 AN: 5150

South Asian (SAS) AF: 0.345 AC: 1652 AN: 4794

European-Finnish (FIN) AF: 0.232 AC: 2433 AN: 10486

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.262 AC: 17809 AN: 67892

Other (OTH) AF: 0.248 AC: 523 AN: 2106

Alfa AF: 0.234 Hom.: 1374

Bravo AF: 0.222

Asia WGS AF: 0.300 AC: 1041 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.4
DANN	Benign	0.36
PhyloP100		-0.018
Mutation Taster		=100/0	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: rs5030039; hg19: chr3-186448159;