rs710448

Positions:

• chr3-186735096-A-G

Variant summary

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

The NM_001102416.3(KNG1):​c.930+2422A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 152,098 control chromosomes in the GnomAD database, including 10,686 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 0.37 (10686 hom., cov: 32)
• Consequence: KNG1 NM_001102416.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.12

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNG1	NM_001102416.3	c.930+2422A>G		intron_variant		ENST00000644859.2	NP_001095886.1
KNG1	NM_000893.4	c.930+2422A>G		intron_variant			NP_000884.1
KNG1	NM_001166451.2	c.822+2422A>G		intron_variant			NP_001159923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2	c.930+2422A>G		intron_variant			NM_001102416.3	ENSP00000493985
HRG-AS1	ENST00000630178.2	n.135+8607T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56668 AN: 151980 Hom.: 10685 Cov.: 32

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.580

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.336

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.477

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.363

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

GnomAD4 genome AF: 0.373 AC: 56708 AN: 152098 Hom.: 10686 Cov.: 32 AF XY: 0.371 AC XY: 27544 AN XY: 74338

Gnomad4 AFR AF: 0.379

Gnomad4 AMR AF: 0.326

Gnomad4 ASJ AF: 0.336

Gnomad4 EAS AF: 0.340

Gnomad4 SAS AF: 0.478

Gnomad4 FIN AF: 0.364

Gnomad4 NFE AF: 0.375

Gnomad4 OTH AF: 0.363

Alfa AF: 0.392 Hom.: 1727

Bravo AF: 0.367

Asia WGS AF: 0.417 AC: 1451 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.9
DANN	Benign	0.46

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: rs710448; hg19: chr3-186452885;