3-186721146-C-A

Variant names:

• chr3-186721146-C-A
• rs1624230
• NM_001102416.3:c.306+931C>A

Variant summary

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

The NM_001102416.3(KNG1):​c.306+931C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 151,800 control chromosomes in the GnomAD database, including 13,955 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 0.42 (13955 hom., cov: 31)
  • Exomes 𝑓: 0.30 (0 hom.)
• Consequence: KNG1 NM_001102416.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.28
• Publications: 11 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=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001102416.3. 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.306+931C>A		intron	N/A	NP_001095886.1
	KNG1	NM_000893.4		c.306+931C>A		intron	N/A	NP_000884.1
	KNG1	NM_001166451.2		c.306+931C>A		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.306+931C>A		intron	N/A	ENSP00000493985.1
	KNG1	ENST00000287611.8	TSL:1	c.306+931C>A		intron	N/A	ENSP00000287611.2
	KNG1	ENST00000447445.1	TSL:3	c.306+931C>A		intron	N/A	ENSP00000396025.1

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64155 AN: 151672 Hom.: 13949 Cov.: 31

Gnomad AFR AF: 0.484

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.612

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.401

GnomAD4 exome AF: 0.300 AC: 3 AN: 10 Hom.: 0 AF XY: 0.333 AC XY: 2 AN XY: 6

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.375 AC: 3 AN: 8

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.423 AC: 64198 AN: 151790 Hom.: 13955 Cov.: 31 AF XY: 0.422 AC XY: 31342 AN XY: 74216

African (AFR) AF: 0.484 AC: 20009 AN: 41318

American (AMR) AF: 0.357 AC: 5452 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1266 AN: 3470

East Asian (EAS) AF: 0.410 AC: 2114 AN: 5152

South Asian (SAS) AF: 0.610 AC: 2931 AN: 4802

European-Finnish (FIN) AF: 0.385 AC: 4071 AN: 10564

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.396 AC: 26905 AN: 67918

Other (OTH) AF: 0.400 AC: 843 AN: 2108

Alfa AF: 0.402 Hom.: 34601

Bravo AF: 0.417

Asia WGS AF: 0.509 AC: 1769 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.3
DANN	Benign	0.72
PhyloP100		-1.3
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: rs1624230; hg19: chr3-186438935;