6-41158663-C-A

Variant names:

• chr6-41158663-C-A
• ENST00000338469.3:c.600G>T

Variant summary

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

The NM_001271821.2(TREM2):​c.600G>T​(p.Trp200Cys) 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 1,458,044 control chromosomes in the GnomAD database, with no homozygous occurrence. 9/12 in silico tools predict 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 the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TREM2 NM_001271821.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.406

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREM2	NM_018965.4	c.*101G>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000373113.8	NP_061838.1
TREM2	NM_001271821.2	c.600G>T	p.Trp200Cys	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.600G>T	p.Trp200Cys	missense_variant	Exon 4 of 4	1		ENSP00000342651.4
TREM2	ENST00000373113	c.*101G>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_018965.4	ENSP00000362205.3
TREM2	ENST00000373122	c.*165G>T		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000362214.4
ENSG00000290034	ENST00000702590.1	n.364+3100C>A		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458044 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724878

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: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.5
DANN	Benign	0.83
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0095	T
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-1.1	T
Polyphen		1.0	D
Vest4		0.51
MutPred		0.63		Loss of catalytic residue at L198 (P = 0.0064);
MVP		0.38
ClinPred		0.095	T
GERP RS		2.1

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-41126401;