NM_001318789.2:c.597T>C

Variant names:

• chr4-153703504-T-C
• rs3804099
• NM_001318789.2:c.597T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001318789.2(TLR2):​c.597T>C​(p.Asn199Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.435 in 1,613,578 control chromosomes in the GnomAD database, including 155,661 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 0.47 (17482 hom., cov: 32)
  • Exomes 𝑓: 0.43 (138179 hom.)
• Consequence: TLR2 NM_001318789.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided U:1 B:1
• Conservation: PhyloP100: -0.718
• Publications: 324 publications found

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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 4-153703504-T-C is Benign according to our data. Variant chr4-153703504-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3060911.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.718 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.613 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR2	NM_001318789.2	MANE Select	c.597T>C	p.Asn199Asn	synonymous	Exon 3 of 3	NP_001305718.1
	TLR2	NM_001318787.2		c.597T>C	p.Asn199Asn	synonymous	Exon 4 of 4	NP_001305716.1
	TLR2	NM_001318790.2		c.597T>C	p.Asn199Asn	synonymous	Exon 3 of 3	NP_001305719.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR2	ENST00000642700.2	MANE Select	c.597T>C	p.Asn199Asn	synonymous	Exon 3 of 3	ENSP00000494425.1
	TLR2	ENST00000260010.7	TSL:6	c.597T>C	p.Asn199Asn	synonymous	Exon 3 of 3	ENSP00000260010.6
	TLR2	ENST00000642580.1		c.597T>C	p.Asn199Asn	synonymous	Exon 3 of 3	ENSP00000495339.1

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71322 AN: 151978 Hom.: 17450 Cov.: 32

Gnomad AFR AF: 0.619

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.479

GnomAD2 exomes AF: 0.405 AC: 101488 AN: 250696 AF XY: 0.404

Gnomad AFR exome AF: 0.612

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.434

Gnomad EAS exome AF: 0.289

Gnomad FIN exome AF: 0.375

Gnomad NFE exome AF: 0.440

Gnomad OTH exome AF: 0.423

GnomAD4 exome AF: 0.432 AC: 630646 AN: 1461482 Hom.: 138179 Cov.: 51 AF XY: 0.429 AC XY: 311733 AN XY: 727018

African (AFR) AF: 0.617 AC: 20657 AN: 33468

American (AMR) AF: 0.333 AC: 14879 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 11273 AN: 26126

East Asian (EAS) AF: 0.304 AC: 12051 AN: 39676

South Asian (SAS) AF: 0.332 AC: 28586 AN: 86160

European-Finnish (FIN) AF: 0.376 AC: 20089 AN: 53360

Middle Eastern (MID) AF: 0.454 AC: 2618 AN: 5768

European-Non Finnish (NFE) AF: 0.445 AC: 494518 AN: 1111860

Other (OTH) AF: 0.430 AC: 25975 AN: 60382

GnomAD4 genome AF: 0.469 AC: 71398 AN: 152096 Hom.: 17482 Cov.: 32 AF XY: 0.461 AC XY: 34275 AN XY: 74322

African (AFR) AF: 0.619 AC: 25680 AN: 41468

American (AMR) AF: 0.380 AC: 5811 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1540 AN: 3468

East Asian (EAS) AF: 0.287 AC: 1488 AN: 5184

South Asian (SAS) AF: 0.327 AC: 1576 AN: 4826

European-Finnish (FIN) AF: 0.379 AC: 4009 AN: 10574

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.439 AC: 29862 AN: 67978

Other (OTH) AF: 0.475 AC: 999 AN: 2104

Alfa AF: 0.448 Hom.: 49344

Bravo AF: 0.476

Asia WGS AF: 0.305 AC: 1065 AN: 3478

EpiCase AF: 0.444

EpiControl AF: 0.439

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	COVID-19–associated multisystem inflammatory syndrome in adults (1)
-	-	1	TLR2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.45
DANN	Benign	0.25
PhyloP100		-0.72
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3804099; hg19: chr4-154624656; COSMIC: COSV52606497; COSMIC: COSV52606497;