Variant 4-153704799-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001318789.2(TLR2):c.1892C>A(p.Pro631His) variant causes a missense change. The variant allele was found at a frequency of 0.0346 in 1,613,762 control chromosomes in the GnomAD database, including 1,139 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.027 ( 75 hom., cov: 32)

Exomes 𝑓: 0.035 ( 1064 hom. )

Consequence

TLR2
NM_001318789.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.09

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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0063203275).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0275 (4173/151976) while in subpopulation NFE AF= 0.0414 (2815/67960). AF 95% confidence interval is 0.0401. There are 75 homozygotes in gnomad4. There are 2008 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 75 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR2	NM_001318789.2 linkuse as main transcript	c.1892C>A	p.Pro631His	missense_variant	3/3	ENST00000642700.2	NP_001305718.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLR2	ENST00000642700.2 linkuse as main transcript	c.1892C>A	p.Pro631His	missense_variant	3/3		NM_001318789.2	ENSP00000494425	P1

Frequencies

GnomAD3 genomes

AF:

0.0275

AC:

4176

AN:

151858

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00740

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0170

Gnomad ASJ

AF:

0.0279

Gnomad EAS

AF:

0.000773

Gnomad SAS

AF:

0.0102

Gnomad FIN

AF:

0.0550

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.0414

Gnomad OTH

AF:

0.0182

GnomAD3 exomes

AF:

0.0278

AC:

6969

AN:

250972

Hom.:

121

AF XY:

0.0290

AC XY:

3928

AN XY:

135670

show subpopulations

Gnomad AFR exome

AF:

0.00690

Gnomad AMR exome

AF:

0.0115

Gnomad ASJ exome

AF:

0.0239

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0139

Gnomad FIN exome

AF:

0.0550

Gnomad NFE exome

AF:

0.0391

Gnomad OTH exome

AF:

0.0271

GnomAD4 exome

AF:

0.0354

AC:

51696

AN:

1461786

Hom.:

1064

Cov.:

AF XY:

0.0349

AC XY:

25372

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00576

Gnomad4 AMR exome

AF:

0.0124

Gnomad4 ASJ exome

AF:

0.0226

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0135

Gnomad4 FIN exome

AF:

0.0532

Gnomad4 NFE exome

AF:

0.0398

Gnomad4 OTH exome

AF:

0.0322

GnomAD4 genome

AF:

0.0275

AC:

4173

AN:

151976

Hom.:

Cov.:

AF XY:

0.0270

AC XY:

2008

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.00738

Gnomad4 AMR

AF:

0.0170

Gnomad4 ASJ

AF:

0.0279

Gnomad4 EAS

AF:

0.000775

Gnomad4 SAS

AF:

0.0100

Gnomad4 FIN

AF:

0.0550

Gnomad4 NFE

AF:

0.0414

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0350

Hom.:

Bravo

AF:

0.0236

TwinsUK

AF:

0.0353

AC:

131

ALSPAC

AF:

0.0348

AC:

134

ESP6500AA

AF:

0.00704

AC:

ESP6500EA

AF:

0.0412

AC:

354

ExAC

AF:

0.0274

AC:

3327

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0385

EpiControl

AF:

0.0383

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;T;T;T

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

.;.;.;D

MetaRNN

Benign

0.0063

T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Pathogenic

3.3

M;M;M;M

MutationTaster

Benign

1.0

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-4.9

.;.;.;D

REVEL

Benign

0.25

Sift

Uncertain

0.0010

.;.;.;D

Sift4G

Uncertain

0.0020

.;.;.;D

Polyphen

1.0

D;D;D;D

Vest4

0.18

MPC

0.43

ClinPred

0.028

GERP RS

5.7

Varity_R

0.62

gMVP

0.61

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over