rs5743704

chr4-153704799-C-Achr4-153704799-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.09

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]

ACMG classification

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 GnomAd at 75 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR2	NM_001318789.2	c.1892C>A	p.Pro631His	missense_variant	3/3	ENST00000642700.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0275 AC: 4176 AN: 151858 Hom.: 75 Cov.: 32

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

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.: 34 AF XY: 0.0349 AC XY: 25372 AN XY: 727192

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.: 75 Cov.: 32 AF XY: 0.0270 AC XY: 2008 AN XY: 74274

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.: 69

Bravo AF: 0.0236

TwinsUK AF: 0.0353 AC: 131

ALSPAC AF: 0.0348 AC: 134

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.0412 AC: 354

ExAC AF: 0.0274 AC: 3327

Asia WGS AF: 0.00491 AC: 17 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	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	26
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	D
MetaRNN	Benign	0.0063	T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Pathogenic	3.3	M;M;M;M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.47	T
Polyphen		1.0	D;D;D;D
Vest4		0.18
MPC		0.43
ClinPred		0.028	T
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

Other links and lift over

dbSNP: rs5743704; hg19: chr4-154625951;