6-41158616-G-C

Variant names:

• chr6-41158616-G-C
• rs761884997
• ENST00000338469.3:c.647C>G

Variant summary

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

The NM_001271821.2(TREM2):​c.647C>G​(p.Ala216Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 10/12 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A216V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TREM2 NM_001271821.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.593

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=0.058023423).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREM2	NM_018965.4	c.*148C>G		3_prime_UTR_variant	Exon 5 of 5	ENST00000373113.8	NP_061838.1
TREM2	NM_001271821.2	c.647C>G	p.Ala216Gly	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.647C>G	p.Ala216Gly	missense_variant	Exon 4 of 4	1		ENSP00000342651.4
TREM2	ENST00000373113	c.*148C>G		3_prime_UTR_variant	Exon 5 of 5	1	NM_018965.4	ENSP00000362205.3
TREM2	ENST00000373122	c.*212C>G		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000362214.4
ENSG00000290034	ENST00000702590.1	n.364+3053G>C		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.35
DANN	Benign	0.81
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.98	T
Polyphen		0.14	B
Vest4		0.061
MutPred		0.22		Gain of relative solvent accessibility (P = 0.0166);
MVP		0.14
ClinPred		0.13	T
GERP RS		0.28

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: rs761884997; hg19: chr6-41126354;