6-41158917-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018965.4(TREM2):c.632T>C(p.Leu211Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,614,148 control chromosomes in the GnomAD database, including 854 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L211L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.039 ( 339 hom., cov: 32)

Exomes 𝑓: 0.0080 ( 515 hom. )

Consequence

TREM2
NM_018965.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.33

Publications

64 publications found

Variant links:

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: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TREM2 links:

ENSG00000290034 (HGNC:):

ENSG00000290034 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014629364).

BP6

Variant 6-41158917-A-G is Benign according to our data. Variant chr6-41158917-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 356676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREM2	NM_018965.4 link	c.632T>C	p.Leu211Pro	missense_variant	Exon 4 of 5	ENST00000373113.8	NP_061838.1	Q9NZC2-1Q5TCX1
TREM2	NM_001271821.2 link	c.483-137T>C		intron_variant	Intron 3 of 3		NP_001258750.1	Q9NZC2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TREM2	ENST00000373113.8 link	c.632T>C	p.Leu211Pro	missense_variant	Exon 4 of 5	1	NM_018965.4	ENSP00000362205.3		Q9NZC2-1

Frequencies

GnomAD3 genomes

AF:

0.0386

AC:

5880

AN:

152142

Hom.:

342

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0195

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00251

Gnomad SAS

AF:

0.0561

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00104

Gnomad OTH

AF:

0.0225

GnomAD2 exomes

AF:

0.0176

AC:

4426

AN:

251454

AF XY:

0.0175

show subpopulations

Gnomad AFR exome

AF:

0.130

Gnomad AMR exome

AF:

0.00928

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00147

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00113

Gnomad OTH exome

AF:

0.00635

GnomAD4 exome

AF:

0.00803

AC:

11743

AN:

1461888

Hom.:

515

Cov.:

AF XY:

0.00908

AC XY:

6606

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.130

AC:

4337

AN:

33480

American (AMR)

AF:

0.0107

AC:

477

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000957

AC:

AN:

26136

East Asian (EAS)

AF:

0.00355

AC:

141

AN:

39700

South Asian (SAS)

AF:

0.0561

AC:

4835

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.0139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000893

AC:

993

AN:

1112010

Other (OTH)

AF:

0.0141

AC:

854

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

785

1569

2354

3138

3923

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

220

440

660

880

1100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0386

AC:

5879

AN:

152260

Hom.:

339

Cov.:

AF XY:

0.0383

AC XY:

2850

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.124

AC:

5169

AN:

41528

American (AMR)

AF:

0.0195

AC:

298

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00251

AC:

AN:

5172

South Asian (SAS)

AF:

0.0549

AC:

265

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00104

AC:

AN:

68024

Other (OTH)

AF:

0.0232

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

261

523

784

1046

1307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0158

Hom.:

333

Bravo

AF:

0.0440

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.116

AC:

513

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.0204

AC:

2471

Asia WGS

AF:

0.0410

AC:

143

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.00196

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 14, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30917570, 25886450) -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Nov 22, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.045

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.018

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.081

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0037

LIST_S2

Benign

0.27

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.94

PhyloP100

-2.3

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.0

REVEL

Benign

0.012

Sift

Benign

0.13

Sift4G

Benign

0.16

Polyphen

0.0010

Vest4

0.035

MPC

0.24

ClinPred

0.0086

GERP RS

-8.9

Varity_R

0.070

gMVP

0.35

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over