Genetic Variant NM_001102416.3:c.307-1053T>C (chr3-186721384-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001102416.3(KNG1):c.307-1053T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 152,142 control chromosomes in the GnomAD database, including 8,188 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 0.32 ( 8183 hom., cov: 32)

Exomes 𝑓: 0.33 ( 5 hom. )

Consequence

KNG1
NM_001102416.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.53

Publications

15 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=-0.99).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
KNG1	NM_001102416.3 link	c.307-1053T>C	intron_variant	Intron 2 of 9	ENST00000644859.2	NP_001095886.1	P01042-1
KNG1	NM_000893.4 link	c.307-1053T>C	intron_variant	Intron 2 of 10		NP_000884.1	P01042-2
KNG1	NM_001166451.2 link	c.307-1053T>C	intron_variant	Intron 2 of 9		NP_001159923.1	P01042-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2 link	c.307-1053T>C		intron_variant	Intron 2 of 9		NM_001102416.3	ENSP00000493985.1		P01042-1

Frequencies

GnomAD3 genomes

AF:

0.319

AC:

48440

AN:

151930

Hom.:

8182

Cov.:

show subpopulations

Gnomad AFR

AF:

0.406

Gnomad AMI

AF:

0.334

Gnomad AMR

AF:

0.238

Gnomad ASJ

AF:

0.281

Gnomad EAS

AF:

0.360

Gnomad SAS

AF:

0.483

Gnomad FIN

AF:

0.251

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.282

Gnomad OTH

AF:

0.313

GnomAD4 exome

AF:

0.330

AC:

AN:

Hom.:

Cov.:

AF XY:

0.338

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.200

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.343

AC:

AN:

Other (OTH)

AF:

0.333

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.319

AC:

48471

AN:

152048

Hom.:

8183

Cov.:

AF XY:

0.318

AC XY:

23603

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.406

AC:

16826

AN:

41452

American (AMR)

AF:

0.238

AC:

3634

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.281

AC:

976

AN:

3470

East Asian (EAS)

AF:

0.360

AC:

1859

AN:

5170

South Asian (SAS)

AF:

0.480

AC:

2307

AN:

4806

European-Finnish (FIN)

AF:

0.251

AC:

2649

AN:

10572

Middle Eastern (MID)

AF:

0.340

AC:

100

AN:

294

European-Non Finnish (NFE)

AF:

0.282

AC:

19156

AN:

67984

Other (OTH)

AF:

0.311

AC:

659

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1684

3368

5051

6735

8419

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

482

964

1446

1928

2410

<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:

0.296

Hom.:

5826

Bravo

AF:

0.317

Asia WGS

AF:

0.416

AC:

1446

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

0.13

(source)

DANN

Benign

0.73

PhyloP100

-2.5

Mutation Taster

=100/0

polymorphism (auto)

(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