Genetic Variant TLR2:p.Ser450Ser (chr4-153704257-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_001318789.2(TLR2):c.1350T>C(p.Ser450Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0807 in 1,614,088 control chromosomes in the GnomAD database, including 6,660 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.071 ( 487 hom., cov: 32)

Exomes 𝑓: 0.082 ( 6173 hom. )

Consequence

TLR2
NM_001318789.2 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity no assertion criteria provided U:1B:1

Conservation

PhyloP100: -4.21

Publications

224 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 4-153704257-T-C is Benign according to our data. Variant chr4-153704257-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3058962.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-4.21 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

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.1350T>C	p.Ser450Ser	synonymous	Exon 3 of 3	NP_001305718.1
TLR2	NM_001318787.2		c.1350T>C	p.Ser450Ser	synonymous	Exon 4 of 4	NP_001305716.1
TLR2	NM_001318790.2		c.1350T>C	p.Ser450Ser	synonymous	Exon 3 of 3	NP_001305719.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TLR2	ENST00000642700.2	MANE Select	c.1350T>C	p.Ser450Ser	synonymous	Exon 3 of 3	ENSP00000494425.1
TLR2	ENST00000260010.7	TSL:6	c.1350T>C	p.Ser450Ser	synonymous	Exon 3 of 3	ENSP00000260010.6
TLR2	ENST00000642580.1		c.1350T>C	p.Ser450Ser	synonymous	Exon 3 of 3	ENSP00000495339.1

Frequencies

GnomAD3 genomes

AF:

0.0711

AC:

10810

AN:

152128

Hom.:

487

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0530

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0706

Gnomad ASJ

AF:

0.0646

Gnomad EAS

AF:

0.254

Gnomad SAS

AF:

0.149

Gnomad FIN

AF:

0.0333

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0691

Gnomad OTH

AF:

0.0832

GnomAD2 exomes

AF:

0.0896

AC:

22502

AN:

251166

AF XY:

0.0931

show subpopulations

Gnomad AFR exome

AF:

0.0516

Gnomad AMR exome

AF:

0.0675

Gnomad ASJ exome

AF:

0.0623

Gnomad EAS exome

AF:

0.259

Gnomad FIN exome

AF:

0.0337

Gnomad NFE exome

AF:

0.0705

Gnomad OTH exome

AF:

0.0828

GnomAD4 exome

AF:

0.0817

AC:

119379

AN:

1461842

Hom.:

6173

Cov.:

AF XY:

0.0840

AC XY:

61061

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.0504

AC:

1687

AN:

33480

American (AMR)

AF:

0.0667

AC:

2985

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0582

AC:

1521

AN:

26134

East Asian (EAS)

AF:

0.279

AC:

11083

AN:

39692

South Asian (SAS)

AF:

0.154

AC:

13246

AN:

86240

European-Finnish (FIN)

AF:

0.0355

AC:

1897

AN:

53416

Middle Eastern (MID)

AF:

0.124

AC:

718

AN:

5768

European-Non Finnish (NFE)

AF:

0.0729

AC:

81038

AN:

1111998

Other (OTH)

AF:

0.0862

AC:

5204

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

6878

13755

20633

27510

34388

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3216

6432

9648

12864

16080

<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:

0.0710

AC:

10815

AN:

152246

Hom.:

487

Cov.:

AF XY:

0.0731

AC XY:

5444

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0531

AC:

2205

AN:

41554

American (AMR)

AF:

0.0704

AC:

1077

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0646

AC:

224

AN:

3468

East Asian (EAS)

AF:

0.254

AC:

1317

AN:

5178

South Asian (SAS)

AF:

0.149

AC:

717

AN:

4824

European-Finnish (FIN)

AF:

0.0333

AC:

353

AN:

10606

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0691

AC:

4700

AN:

68006

Other (OTH)

AF:

0.0833

AC:

176

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

522

1044

1565

2087

2609

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

134

268

402

536

670

<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:

0.0725

Hom.:

1622

Bravo

AF:

0.0729

Asia WGS

AF:

0.177

AC:

614

AN:

3478

EpiCase

AF:

0.0710

EpiControl

AF:

0.0730

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

COVID-19–associated multisystem inflammatory syndrome in adults

Uncertain:1

Jan 01, 2024

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

TLR2-related disorder

Benign:1

Dec 09, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.12

(source)

DANN

Benign

0.44

PhyloP100

-4.2

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

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