Genetic Variant ENST00000338469.3:c.596T>C (chr6-41158667-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000338469.3(TREM2):c.596T>C(p.Leu199Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,459,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TREM2
ENST00000338469.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.971

Variant links:

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]

TREM2 links:

ENSG00000290034 (HGNC:):

ENSG00000290034 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15799794).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREM2	NM_018965.4 link	c.*97T>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000373113.8	NP_061838.1	Q9NZC2-1Q5TCX1
TREM2	NM_001271821.2 link	c.596T>C	p.Leu199Pro	missense_variant	Exon 4 of 4		NP_001258750.1	Q9NZC2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TREM2	ENST00000338469.3 link	c.596T>C	p.Leu199Pro	missense_variant	Exon 4 of 4	1		ENSP00000342651.4	Q9NZC2-2
TREM2	ENST00000373113 link	c.*97T>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_018965.4	ENSP00000362205.3	Q9NZC2-1
TREM2	ENST00000373122 link	c.*161T>C		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000362214.4	Q9NZC2-3
ENSG00000290034	ENST00000702590.1 link	n.364+3104A>G		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000122

AC:

AN:

246262

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

133008

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000999

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000617

AC:

AN:

1459614

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

725806

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000105

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TREM2 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_001271821.1, and corresponds to NM_018965.3:c.*97T>C in the primary transcript. This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 199 of the TREM2 protein (Leu199Pro). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TREM2-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.56

CADD

Benign

8.1

DANN

Benign

0.84

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.19

M_CAP

Benign

0.0050

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.0

Polyphen

0.0080

Vest4

0.34

MutPred

0.57

Gain of sheet (P = 0.0061);

MVP

0.22

ClinPred

0.025

GERP RS

1.7

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over