rs201258663
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_018965.4(TREM2):c.197C>T(p.Thr66Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000539 in 1,614,234 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000053 ( 0 hom. )
Consequence
TREM2
NM_018965.4 missense
NM_018965.4 missense
Scores
5
11
3
Clinical Significance
Conservation
PhyloP100: 5.77
Genes affected
TREM2 (HGNC:17761): (triggering receptor expressed on myeloid cells 2) This gene encodes a membrane protein that forms a receptor signaling complex with the TYRO protein tyrosine kinase binding protein. The encoded protein functions in immune response and may be involved in chronic inflammation by triggering the production of constitutive inflammatory cytokines. Defects in this gene are a cause of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Nov 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-41161457-G-A is Pathogenic according to our data. Variant chr6-41161457-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 192242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TREM2 | NM_018965.4 | c.197C>T | p.Thr66Met | missense_variant | 2/5 | ENST00000373113.8 | NP_061838.1 | |
TREM2 | NM_001271821.2 | c.197C>T | p.Thr66Met | missense_variant | 2/4 | NP_001258750.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TREM2 | ENST00000373113.8 | c.197C>T | p.Thr66Met | missense_variant | 2/5 | 1 | NM_018965.4 | ENSP00000362205.3 | ||
TREM2 | ENST00000373122.8 | c.197C>T | p.Thr66Met | missense_variant | 2/5 | 1 | ENSP00000362214.4 | |||
TREM2 | ENST00000338469.3 | c.197C>T | p.Thr66Met | missense_variant | 2/4 | 1 | ENSP00000342651.4 | |||
ENSG00000290034 | ENST00000702590.1 | n.364+5894G>A | intron_variant |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152228Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251358Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135854
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GnomAD4 exome AF: 0.0000534 AC: 78AN: 1461888Hom.: 0 Cov.: 32 AF XY: 0.0000633 AC XY: 46AN XY: 727242
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GnomAD4 genome AF: 0.0000591 AC: 9AN: 152346Hom.: 0 Cov.: 32 AF XY: 0.0000805 AC XY: 6AN XY: 74504
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen | - | The detected variant has a low frequency in gnomAD (0,005390 %) and ist only reported in heterozygous occurence. Bioinformatic predicition is deleterious (CaddPhred, SIFT, MutationTaster). The variant has been reported in literature before (PMID: 23318515, PMID: 24910390). It was classified as likely pathogenic (PS1, PM1, PM2, PM3). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 27, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 66 of the TREM2 protein (p.Thr66Met). This variant is present in population databases (rs201258663, gnomAD 0.04%). This missense change has been observed in individuals with autosomal dominant Alzheimer disease and/or autosomal recessive frontotemporal dementia (PMID: 23150934, 23318515, 24899047, 29557178). ClinVar contains an entry for this variant (Variation ID: 192242). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TREM2 function (PMID: 24990881, 25615530, 28559417). For these reasons, this variant has been classified as Pathogenic. - |
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;M
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;D;D
Vest4
MVP
MPC
0.66
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at