3-186741438-A-G

Variant names:

• chr3-186741438-A-G
• rs698078
• NM_001102416.3:c.1126-84A>G

Variant summary

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

The NM_001102416.3(KNG1):​c.1126-84A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 1,236,656 control chromosomes in the GnomAD database, including 104,173 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 0.43 (14689 hom., cov: 33)
  • Exomes 𝑓: 0.40 (89484 hom.)
• Consequence: KNG1 NM_001102416.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0820
• Publications: 13 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=-0.92).
• 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: 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.1126-84A>G		intron	N/A	NP_001095886.1
	KNG1	NM_000893.4		c.1126-84A>G		intron	N/A	NP_000884.1
	KNG1	NM_001166451.2		c.1018-84A>G		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.1126-84A>G		intron	N/A	ENSP00000493985.1
	KNG1	ENST00000287611.8	TSL:1	c.1126-84A>G		intron	N/A	ENSP00000287611.2
	KNG1	ENST00000447445.1	TSL:3	c.1018-84A>G		intron	N/A	ENSP00000396025.1

Frequencies

GnomAD3 genomes AF: 0.435 AC: 66046 AN: 151984 Hom.: 14670 Cov.: 33

Gnomad AFR AF: 0.516

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.513

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.356

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.443

GnomAD4 exome AF: 0.403 AC: 437485 AN: 1084554 Hom.: 89484 AF XY: 0.403 AC XY: 220694 AN XY: 547686

African (AFR) AF: 0.523 AC: 12573 AN: 24028

American (AMR) AF: 0.467 AC: 13851 AN: 29684

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 10414 AN: 20292

East Asian (EAS) AF: 0.286 AC: 10402 AN: 36384

South Asian (SAS) AF: 0.375 AC: 24837 AN: 66232

European-Finnish (FIN) AF: 0.376 AC: 18529 AN: 49344

Middle Eastern (MID) AF: 0.433 AC: 1570 AN: 3630

European-Non Finnish (NFE) AF: 0.403 AC: 325877 AN: 808140

Other (OTH) AF: 0.415 AC: 19432 AN: 46820

GnomAD4 genome AF: 0.435 AC: 66116 AN: 152102 Hom.: 14689 Cov.: 33 AF XY: 0.432 AC XY: 32114 AN XY: 74344

African (AFR) AF: 0.516 AC: 21414 AN: 41476

American (AMR) AF: 0.446 AC: 6807 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 1778 AN: 3468

East Asian (EAS) AF: 0.290 AC: 1502 AN: 5188

South Asian (SAS) AF: 0.357 AC: 1723 AN: 4824

European-Finnish (FIN) AF: 0.367 AC: 3873 AN: 10562

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.408 AC: 27751 AN: 67986

Other (OTH) AF: 0.439 AC: 928 AN: 2114

Alfa AF: 0.424 Hom.: 24118

Bravo AF: 0.447

Asia WGS AF: 0.354 AC: 1233 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.7
DANN	Benign	0.53
PhyloP100		0.082
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: rs698078; hg19: chr3-186459227; COSMIC: COSV53979388; COSMIC: COSV53979388;