rs2234256

Variant names:

• chr6-41158917-A-C
• NM_018965.4:c.632T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-41158917-A-C
• chr6-41158917-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018965.4(TREM2):​c.632T>G​(p.Leu211Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. L211P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TREM2 NM_018965.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.33

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046620786).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREM2	NM_018965.4	c.632T>G	p.Leu211Arg	missense_variant	Exon 4 of 5	ENST00000373113.8	NP_061838.1
TREM2	NM_001271821.2	c.483-137T>G		intron_variant	Intron 3 of 3		NP_001258750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TREM2	ENST00000373113.8	c.632T>G	p.Leu211Arg	missense_variant	Exon 4 of 5	1	NM_018965.4	ENSP00000362205.3
TREM2	ENST00000373122	c.*3T>G		3_prime_UTR_variant	Exon 4 of 5	1		ENSP00000362214.4
TREM2	ENST00000338469.3	c.483-137T>G		intron_variant	Intron 3 of 3	1		ENSP00000342651.4
ENSG00000290034	ENST00000702590.1	n.364+3354A>C		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

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: 8.99e-7

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
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.019
DANN	Benign	0.88
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0094	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.030
Sift	Uncertain	0.024	D
Sift4G	Benign	0.074	T
Polyphen		0.0030	B
Vest4		0.14
MutPred		0.18		Loss of stability (P = 0.0262);
MVP		0.15
MPC		0.22
ClinPred		0.086	T
GERP RS		-8.9
Varity_R		0.11
gMVP		0.30

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: chr6-41126655;