4-153705165-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001318789.2(TLR2):c.2258G>A(p.Arg753Gln) variant causes a missense change. The variant allele was found at a frequency of 0.025 in 1,614,052 control chromosomes in the GnomAD database, including 632 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

Frequency

Genomes: 𝑓 0.018 ( 40 hom., cov: 32)

Exomes 𝑓: 0.026 ( 592 hom. )

Consequence

TLR2
NM_001318789.2 missense

Scores

Clinical Significance

risk factor no assertion criteria provided O:1

Conservation

PhyloP100: 6.79

Publications

665 publications found

Variant links:

Genes affected

TLR2 (HGNC:11848): (toll like receptor 2) The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. This protein is a cell-surface protein that can form heterodimers with other TLR family members to recognize conserved molecules derived from microorganisms known as pathogen-associated molecular patterns (PAMPs). Activation of TLRs by PAMPs leads to an up-regulation of signaling pathways to modulate the host's inflammatory response. This gene is also thought to promote apoptosis in response to bacterial lipoproteins. This gene has been implicated in the pathogenesis of several autoimmune diseases. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

TLR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009150982).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0177 (2699/152180) while in subpopulation NFE AF = 0.0294 (1998/67988). AF 95% confidence interval is 0.0283. There are 40 homozygotes in GnomAd4. There are 1268 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 40 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318789.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TLR2	NM_001318789.2	MANE Select	c.2258G>A	p.Arg753Gln	missense	Exon 3 of 3	NP_001305718.1
TLR2	NM_001318787.2		c.2258G>A	p.Arg753Gln	missense	Exon 4 of 4	NP_001305716.1
TLR2	NM_001318790.2		c.2258G>A	p.Arg753Gln	missense	Exon 3 of 3	NP_001305719.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TLR2	ENST00000642700.2	MANE Select	c.2258G>A	p.Arg753Gln	missense	Exon 3 of 3	ENSP00000494425.1
TLR2	ENST00000260010.7	TSL:6	c.2258G>A	p.Arg753Gln	missense	Exon 3 of 3	ENSP00000260010.6
TLR2	ENST00000642580.1		c.2258G>A	p.Arg753Gln	missense	Exon 3 of 3	ENSP00000495339.1

Frequencies

GnomAD3 genomes

AF:

0.0178

AC:

2701

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00418

Gnomad AMI

AF:

0.0231

Gnomad AMR

AF:

0.00831

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0299

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0294

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.0174

AC:

4375

AN:

251060

AF XY:

0.0173

show subpopulations

Gnomad AFR exome

AF:

0.00388

Gnomad AMR exome

AF:

0.00561

Gnomad ASJ exome

AF:

0.00746

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.0311

Gnomad NFE exome

AF:

0.0281

Gnomad OTH exome

AF:

0.0166

GnomAD4 exome

AF:

0.0257

AC:

37626

AN:

1461872

Hom.:

592

Cov.:

AF XY:

0.0250

AC XY:

18208

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00379

AC:

127

AN:

33480

American (AMR)

AF:

0.00606

AC:

271

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00765

AC:

200

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.00245

AC:

211

AN:

86256

European-Finnish (FIN)

AF:

0.0322

AC:

1719

AN:

53412

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0305

AC:

33881

AN:

1112000

Other (OTH)

AF:

0.0198

AC:

1195

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

2178

4356

6534

8712

10890

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1248

2496

3744

4992

6240

<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:

0.0177

AC:

2699

AN:

152180

Hom.:

Cov.:

AF XY:

0.0170

AC XY:

1268

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.00417

AC:

173

AN:

41532

American (AMR)

AF:

0.00824

AC:

126

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5168

South Asian (SAS)

AF:

0.00269

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0299

AC:

316

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0294

AC:

1998

AN:

67988

Other (OTH)

AF:

0.0114

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

130

260

391

521

651

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0248

Hom.:

Bravo

AF:

0.0151

TwinsUK

AF:

0.0359

AC:

133

ALSPAC

AF:

0.0301

AC:

116

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.0309

AC:

266

ExAC

AF:

0.0172

AC:

2093

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0261

EpiControl

AF:

0.0219

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Mycobacterium tuberculosis, susceptibility to

Other:1

Nov 02, 2012

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.25

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0092

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.8

PhyloP100

6.8

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.24

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.016

Polyphen

1.0

Vest4

0.20

MPC

0.43

ClinPred

0.014

GERP RS

5.6

Varity_R

0.81

gMVP

0.58

Mutation Taster

=78/22

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over