ENST00000338469.3:c.601C>G

Variant names:

• chr6-41158662-G-C
• rs758041103
• ENST00000338469.3:c.601C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000338469.3(TREM2):​c.601C>G​(p.Gln201Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,720 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: 6.9e-7 (0 hom.)
• Consequence: TREM2 ENST00000338469.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.742

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]

ENSG00000290034 (HGNC:):

ACMG classification

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=0.0866175).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREM2	NM_018965.4	c.*102C>G		3_prime_UTR_variant	Exon 5 of 5	ENST00000373113.8	NP_061838.1
TREM2	NM_001271821.2	c.601C>G	p.Gln201Glu	missense_variant	Exon 4 of 4		NP_001258750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TREM2	ENST00000338469.3	c.601C>G	p.Gln201Glu	missense_variant	Exon 4 of 4	1		ENSP00000342651.4
TREM2	ENST00000373113	c.*102C>G		3_prime_UTR_variant	Exon 5 of 5	1	NM_018965.4	ENSP00000362205.3
TREM2	ENST00000373122	c.*166C>G		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000362214.4
ENSG00000290034	ENST00000702590.1	n.364+3099G>C		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457720 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724674

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in a non-coding region of the TREM2 gene. It does not change the encoded amino acid sequence of the TREM2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TREM2-related conditions. 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	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	4.2
DANN	Benign	0.95
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-0.99	T
Polyphen		0.10	B
Vest4		0.21
MutPred		0.34		Gain of relative solvent accessibility (P = 0.09);
MVP		0.43
ClinPred		0.077	T
GERP RS		-0.74

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: rs758041103; hg19: chr6-41126400;