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rs5743708

Variant summary

Our verdict is Benign. Variant got -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

4
2
7

Clinical Significance

risk factor no assertion criteria provided O:1

Conservation

PhyloP100: 6.79
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAd at 40 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TLR2NM_001318789.2 linkuse as main transcriptc.2258G>A p.Arg753Gln missense_variant 3/3 ENST00000642700.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TLR2ENST00000642700.2 linkuse as main transcriptc.2258G>A p.Arg753Gln missense_variant 3/3 NM_001318789.2 P1

Frequencies

GnomAD3 genomes
AF:
0.0178
AC:
2701
AN:
152062
Hom.:
40
Cov.:
32
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
GnomAD3 exomes
AF:
0.0174
AC:
4375
AN:
251060
Hom.:
80
AF XY:
0.0173
AC XY:
2355
AN XY:
135790
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 SAS exome
AF:
0.00245
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.:
34
AF XY:
0.0250
AC XY:
18208
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.00379
Gnomad4 AMR exome
AF:
0.00606
Gnomad4 ASJ exome
AF:
0.00765
Gnomad4 EAS exome
AF:
0.000151
Gnomad4 SAS exome
AF:
0.00245
Gnomad4 FIN exome
AF:
0.0322
Gnomad4 NFE exome
AF:
0.0305
Gnomad4 OTH exome
AF:
0.0198
GnomAD4 genome
AF:
0.0177
AC:
2699
AN:
152180
Hom.:
40
Cov.:
32
AF XY:
0.0170
AC XY:
1268
AN XY:
74394
show subpopulations
Gnomad4 AFR
AF:
0.00417
Gnomad4 AMR
AF:
0.00824
Gnomad4 ASJ
AF:
0.00749
Gnomad4 EAS
AF:
0.000387
Gnomad4 SAS
AF:
0.00269
Gnomad4 FIN
AF:
0.0299
Gnomad4 NFE
AF:
0.0294
Gnomad4 OTH
AF:
0.0114
Alfa
AF:
0.0250
Hom.:
39
Bravo
AF:
0.0151
TwinsUK
AF:
0.0359
AC:
133
ALSPAC
AF:
0.0301
AC:
116
ESP6500AA
AF:
0.00522
AC:
23
ESP6500EA
AF:
0.0309
AC:
266
ExAC
AF:
0.0172
AC:
2093
Asia WGS
AF:
0.00202
AC:
7
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
risk factor, no assertion criteria providedliterature onlyOMIMNov 02, 2012- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.39
Cadd
Pathogenic
32
Dann
Pathogenic
1.0
DEOGEN2
Benign
0.25
T;T;T;T;T
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
0.99
D
MetaRNN
Benign
0.0092
T;T;T;T;T
MetaSVM
Benign
-1.2
T
MutationAssessor
Uncertain
2.8
M;M;M;M;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.60
T
Polyphen
1.0
D;D;D;D;.
Vest4
0.20
MPC
0.43
ClinPred
0.014
T
GERP RS
5.6
Varity_R
0.81
gMVP
0.58

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

LitVar

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

Other links and lift over

dbSNP: rs5743708; hg19: chr4-154626317; COSMIC: COSV52605106; COSMIC: COSV52605106; API