dbSNP rs5030094: KNG1:c.*1038T>C (chr3-186743369-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001102416.3(KNG1):c.*1038T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 275,784 control chromosomes in the GnomAD database, including 43 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 0.016 ( 27 hom., cov: 33)

Exomes 𝑓: 0.015 ( 16 hom. )

Consequence

KNG1
NM_001102416.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.02

Publications

2 publications found

Variant links:

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]

KNG1 links:

HRG-AS1 (HGNC:55915): (HRG and FETUB antisense RNA 1)

HRG-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.016 (2444/152354) while in subpopulation NFE AF = 0.0191 (1301/68028). AF 95% confidence interval is 0.0183. There are 27 homozygotes in GnomAd4. There are 1101 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 27 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
KNG1	NM_001102416.3 link	c.*1038T>C	3_prime_UTR_variant	Exon 10 of 10	ENST00000644859.2	NP_001095886.1
KNG1	NM_000893.4 link	c.1204-336T>C	intron_variant	Intron 10 of 10		NP_000884.1
KNG1	NM_001166451.2 link	c.1096-336T>C	intron_variant	Intron 9 of 9		NP_001159923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2 link	c.*1038T>C		3_prime_UTR_variant	Exon 10 of 10		NM_001102416.3	ENSP00000493985.1

Frequencies

GnomAD3 genomes

AF:

0.0160

AC:

2438

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0158

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.0164

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.00846

Gnomad SAS

AF:

0.00662

Gnomad FIN

AF:

0.00442

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0191

Gnomad OTH

AF:

0.0167

GnomAD4 exome

AF:

0.0146

AC:

1796

AN:

123430

Hom.:

Cov.:

AF XY:

0.0134

AC XY:

875

AN XY:

65170

show subpopulations

African (AFR)

AF:

0.0133

AC:

AN:

4138

American (AMR)

AF:

0.0134

AC:

AN:

5730

Ashkenazi Jewish (ASJ)

AF:

0.0143

AC:

AN:

3290

East Asian (EAS)

AF:

0.0105

AC:

AN:

6582

South Asian (SAS)

AF:

0.00470

AC:

AN:

17222

European-Finnish (FIN)

AF:

0.00439

AC:

AN:

5236

Middle Eastern (MID)

AF:

0.0185

AC:

AN:

432

European-Non Finnish (NFE)

AF:

0.0178

AC:

1326

AN:

74320

Other (OTH)

AF:

0.0170

AC:

110

AN:

6480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

184

276

368

460

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0160

AC:

2444

AN:

152354

Hom.:

Cov.:

AF XY:

0.0148

AC XY:

1101

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0158

AC:

655

AN:

41580

American (AMR)

AF:

0.0164

AC:

251

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

AN:

3470

East Asian (EAS)

AF:

0.00828

AC:

AN:

5192

South Asian (SAS)

AF:

0.00662

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00442

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0191

AC:

1301

AN:

68028

Other (OTH)

AF:

0.0198

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

133

266

398

531

664

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0182

Hom.:

Bravo

AF:

0.0167

Asia WGS

AF:

0.0200

AC:

AN:

3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.14

(source)

DANN

Benign

0.67

PhyloP100

-2.0

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over