Genetic Variant NM_001102416.3:c.293A>T (chr3-186720202-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001102416.3(KNG1):c.293A>T(p.Asp98Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KNG1
NM_001102416.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.504

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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNG1	NM_001102416.3 link	c.293A>T	p.Asp98Val	missense_variant	Exon 2 of 10	ENST00000644859.2	NP_001095886.1	P01042-1
KNG1	NM_000893.4 link	c.293A>T	p.Asp98Val	missense_variant	Exon 2 of 11		NP_000884.1	P01042-2
KNG1	NM_001166451.2 link	c.293A>T	p.Asp98Val	missense_variant	Exon 2 of 10		NP_001159923.1	P01042-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2 link	c.293A>T	p.Asp98Val	missense_variant	Exon 2 of 10		NM_001102416.3	ENSP00000493985.1		P01042-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251010

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1457240

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

725326

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 02, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.293A>T (p.D98V) alteration is located in exon 2 (coding exon 2) of the KNG1 gene. This alteration results from a A to T substitution at nucleotide position 293, causing the aspartic acid (D) at amino acid position 98 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.36

.;T;.;.;T

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.074

LIST_S2

Uncertain

0.90

.;.;D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.34

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

M;M;M;M;M

PrimateAI

Benign

0.27

PROVEAN

Pathogenic

-4.8

.;D;D;D;.

REVEL

Benign

0.076

Sift

Uncertain

0.014

.;D;D;D;.

Sift4G

Uncertain

0.0050

.;D;D;D;.

Polyphen

0.95

P;P;.;P;P

Vest4

0.24, 0.26, 0.25

MutPred

0.53

Gain of glycosylation at Y96 (P = 0.0093);Gain of glycosylation at Y96 (P = 0.0093);Gain of glycosylation at Y96 (P = 0.0093);Gain of glycosylation at Y96 (P = 0.0093);Gain of glycosylation at Y96 (P = 0.0093);

MVP

0.61

MPC

0.20

ClinPred

0.63

GERP RS

3.3

Varity_R

0.26

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.21

Position offset: -13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over