NM_001102416.3:c.930+773T>C

Variant names:

• chr3-186733447-T-C
• rs4686799
• NM_001102416.3:c.930+773T>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.930+773T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.773 in 151,832 control chromosomes in the GnomAD database, including 45,472 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 0.77 (45472 hom., cov: 29)
• Consequence: KNG1 NM_001102416.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.194
• Publications: 15 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=-0.97).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.814 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNG1	NM_001102416.3	c.930+773T>C		intron_variant	Intron 7 of 9	ENST00000644859.2	NP_001095886.1
KNG1	NM_000893.4	c.930+773T>C		intron_variant	Intron 7 of 10		NP_000884.1
KNG1	NM_001166451.2	c.822+773T>C		intron_variant	Intron 6 of 9		NP_001159923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2	c.930+773T>C		intron_variant	Intron 7 of 9		NM_001102416.3	ENSP00000493985.1

Frequencies

GnomAD3 genomes AF: 0.774 AC: 117354 AN: 151714 Hom.: 45439 Cov.: 29

Gnomad AFR AF: 0.812

Gnomad AMI AF: 0.766

Gnomad AMR AF: 0.766

Gnomad ASJ AF: 0.773

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.836

Gnomad FIN AF: 0.725

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.764

Gnomad OTH AF: 0.799

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

GnomAD4 genome AF: 0.773 AC: 117442 AN: 151832 Hom.: 45472 Cov.: 29 AF XY: 0.771 AC XY: 57221 AN XY: 74182

African (AFR) AF: 0.812 AC: 33608 AN: 41394

American (AMR) AF: 0.766 AC: 11669 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.773 AC: 2685 AN: 3472

East Asian (EAS) AF: 0.645 AC: 3317 AN: 5140

South Asian (SAS) AF: 0.836 AC: 4028 AN: 4818

European-Finnish (FIN) AF: 0.725 AC: 7627 AN: 10514

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.764 AC: 51877 AN: 67942

Other (OTH) AF: 0.796 AC: 1681 AN: 2112

Alfa AF: 0.770 Hom.: 201448

Bravo AF: 0.777

Asia WGS AF: 0.766 AC: 2663 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	4.0
DANN	Benign	0.67
PhyloP100		-0.19
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: rs4686799; hg19: chr3-186451236;