chr3-186725117-G-A

Position:

• chr3-186725117-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS2_Supporting

The NM_001102416.3(KNG1):​c.421G>A​(p.Asp141Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: KNG1 NM_001102416.3 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.240

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10881111).
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNG1	NM_001102416.3	c.421G>A	p.Asp141Asn	missense_variant	4/10	ENST00000644859.2	NP_001095886.1
KNG1	NM_000893.4	c.421G>A	p.Asp141Asn	missense_variant	4/11		NP_000884.1
KNG1	NM_001166451.2	c.421G>A	p.Asp141Asn	missense_variant	4/10		NP_001159923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2	c.421G>A	p.Asp141Asn	missense_variant	4/10		NM_001102416.3	ENSP00000493985
HRG-AS1	ENST00000630178.2	n.136-6548C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461816 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Hereditary angioedema with normal C1Inh Other:1

not provided, no classification provided

literature only

CeMIA

Feb 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.20
DANN	Benign	0.82
DEOGEN2	Benign	0.27	.;T;.;.;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.16	.;.;T;T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.54	.;N;N;N;.
REVEL	Benign	0.030
Sift	Benign	0.51	.;T;T;T;.
Sift4G	Benign	0.53	.;T;T;T;.
Polyphen		0.0010	B;B;.;B;B
Vest4		0.058, 0.089, 0.098
MutPred		0.51		Loss of glycosylation at T137 (P = 0.0538);Loss of glycosylation at T137 (P = 0.0538);Loss of glycosylation at T137 (P = 0.0538);Loss of glycosylation at T137 (P = 0.0538);Loss of glycosylation at T137 (P = 0.0538);
MVP		0.34
MPC		0.061
ClinPred		0.082	T
GERP RS		-8.1
Varity_R		0.027
gMVP		0.31

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: rs1579116763; hg19: chr3-186442906; COSMIC: COSV99405626; COSMIC: COSV99405626;