Genetic Variant NM_001102416.3:c.310A>T (chr3-186722440-A-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001102416.3(KNG1):c.310A>T(p.Thr104Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

KNG1
NM_001102416.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.62

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27912176).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KNG1	NM_001102416.3	MANE Select	c.310A>T	p.Thr104Ser	missense	Exon 3 of 10	NP_001095886.1	P01042-1
KNG1	NM_000893.4		c.310A>T	p.Thr104Ser	missense	Exon 3 of 11	NP_000884.1	P01042-2
KNG1	NM_001166451.2		c.310A>T	p.Thr104Ser	missense	Exon 3 of 10	NP_001159923.1	P01042-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KNG1	ENST00000644859.2	MANE Select	c.310A>T	p.Thr104Ser	missense	Exon 3 of 10	ENSP00000493985.1	P01042-1
KNG1	ENST00000287611.8	TSL:1	c.310A>T	p.Thr104Ser	missense	Exon 3 of 11	ENSP00000287611.2	P01042-2
KNG1	ENST00000897809.1		c.310A>T	p.Thr104Ser	missense	Exon 3 of 10	ENSP00000567868.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

Eigen

Benign

0.012

Eigen_PC

Benign

-0.042

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.83

M_CAP

Benign

0.010

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.3

PhyloP100

1.6

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.3

REVEL

Benign

0.069

Sift

Benign

0.14

Sift4G

Uncertain

0.011

Polyphen

0.75

Vest4

0.17

MutPred

0.37

Gain of glycosylation at T104 (P = 0.015)

MVP

0.44

MPC

0.095

ClinPred

0.89

GERP RS

3.2

Varity_R

0.080

gMVP

0.25

Mutation Taster

=92/8

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over