chr6-41158607-C-T

Variant names:

• chr6-41158607-C-T
• rs1232354245
• ENST00000338469.3:c.656G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001271821.2(TREM2):​c.656G>A​(p.Gly219Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000276 in 1,415,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G219C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: TREM2 NM_001271821.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0350
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000290034 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05068192).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271821.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TREM2	NM_018965.4	MANE Select	c.*157G>A		3_prime_UTR	Exon 5 of 5	NP_061838.1	Q5TCX1
	TREM2	NM_001271821.2		c.656G>A	p.Gly219Asp	missense	Exon 4 of 4	NP_001258750.1	Q9NZC2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TREM2	ENST00000338469.3	TSL:1	c.656G>A	p.Gly219Asp	missense	Exon 4 of 4	ENSP00000342651.4	Q9NZC2-2
	TREM2	ENST00000373113.8	TSL:1 MANE Select	c.*157G>A		3_prime_UTR	Exon 5 of 5	ENSP00000362205.3	Q9NZC2-1
	TREM2	ENST00000373122.8	TSL:1	c.*221G>A		3_prime_UTR	Exon 5 of 5	ENSP00000362214.4	Q9NZC2-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 181284 AF XY: 0.0000209

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000769

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000134

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000276 AC: 39 AN: 1415232 Hom.: 0 Cov.: 31 AF XY: 0.0000272 AC XY: 19 AN XY: 699546

African (AFR) AF: 0.00 AC: 0 AN: 32338

American (AMR) AF: 0.00 AC: 0 AN: 36888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25320

East Asian (EAS) AF: 0.0000270 AC: 1 AN: 37040

South Asian (SAS) AF: 0.00 AC: 0 AN: 81254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.0000331 AC: 36 AN: 1087252

Other (OTH) AF: 0.0000341 AC: 2 AN: 58724

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.77
DANN	Benign	0.22
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.035
Polyphen		0.0	B
Vest4		0.091
MutPred		0.32		Loss of sheet (P = 0.0457)
MVP		0.061
ClinPred		0.0070	T
GERP RS		0.14
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1232354245; hg19: chr6-41126345;