6-41161367-G-T

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.287C>A(p.Thr96Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00728 in 1,614,204 control chromosomes in the GnomAD database, including 623 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T96M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.036 ( 317 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 306 hom. )

Consequence

TREM2
NM_018965.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.77

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 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=0.0032537878).

BP6

Variant 6-41161367-G-T is Benign according to our data. Variant chr6-41161367-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 356678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-41161367-G-T is described in Lovd as [Benign]. Variant chr6-41161367-G-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREM2	NM_018965.4 link	c.287C>A	p.Thr96Lys	missense_variant	Exon 2 of 5	ENST00000373113.8	NP_061838.1	Q9NZC2-1Q5TCX1
TREM2	NM_001271821.2 link	c.287C>A	p.Thr96Lys	missense_variant	Exon 2 of 4		NP_001258750.1	Q9NZC2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TREM2	ENST00000373113.8 link	c.287C>A	p.Thr96Lys	missense_variant	Exon 2 of 5	1	NM_018965.4	ENSP00000362205.3	Q9NZC2-1
TREM2	ENST00000373122.8 link	c.287C>A	p.Thr96Lys	missense_variant	Exon 2 of 5	1		ENSP00000362214.4	Q9NZC2-3
TREM2	ENST00000338469.3 link	c.287C>A	p.Thr96Lys	missense_variant	Exon 2 of 4	1		ENSP00000342651.4	Q9NZC2-2
ENSG00000290034	ENST00000702590.1 link	n.364+5804G>T		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.0360

AC:

5477

AN:

152192

Hom.:

320

Cov.:

show subpopulations

Gnomad AFR

AF:

0.123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0166

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000985

Gnomad OTH

AF:

0.0206

GnomAD2 exomes

AF:

0.00996

AC:

2504

AN:

251476

AF XY:

0.00776

show subpopulations

Gnomad AFR exome

AF:

0.128

Gnomad AMR exome

AF:

0.00775

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00429

AC:

6269

AN:

1461894

Hom.:

306

Cov.:

AF XY:

0.00386

AC XY:

2805

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.127

AC:

4266

AN:

33480

Gnomad4 AMR exome

AF:

0.00890

AC:

398

AN:

44724

Gnomad4 ASJ exome

AF:

0.000957

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.0000252

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.000475

AC:

AN:

86258

Gnomad4 FIN exome

AF:

0.0000187

AC:

AN:

53420

Gnomad4 NFE exome

AF:

0.000840

AC:

934

AN:

1112012

Gnomad4 Remaining exome

AF:

0.00881

AC:

532

AN:

60396

Heterozygous variant carriers

400

800

1200

1600

2000

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

154

308

462

616

770

<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:

0.0360

AC:

5480

AN:

152310

Hom.:

317

Cov.:

AF XY:

0.0346

AC XY:

2574

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.123

AC:

0.122767

AN:

0.122767

Gnomad4 AMR

AF:

0.0166

AC:

0.0165926

AN:

0.0165926

Gnomad4 ASJ

AF:

0.00231

AC:

0.00230681

AN:

0.00230681

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000414

AC:

0.000413907

AN:

0.000413907

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000985

AC:

0.000984889

AN:

0.000984889

Gnomad4 OTH

AF:

0.0203

AC:

0.0203406

AN:

0.0203406

Heterozygous variant carriers

239

478

718

957

1196

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0111

Hom.:

Bravo

AF:

0.0424

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.113

AC:

500

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.0120

AC:

1457

EpiCase

AF:

0.000927

EpiControl

AF:

0.00184

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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: 25042114, 28430856, 28789839, 29723869) -

Sep 12, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

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

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 22, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

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

0.34

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.48

.;T;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.77

T;T;T

MetaRNN

Benign

0.0033

T;T;T

MetaSVM

Uncertain

-0.23

MutationAssessor

Pathogenic

3.1

M;M;M

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-4.5

D;D;D

REVEL

Benign

0.26

Sift

Uncertain

0.0020

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.35

MPC

0.71

ClinPred

0.044

GERP RS

5.5

Varity_R

0.83

gMVP

0.59

Mutation Taster

=74/26

polymorphism (auto)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over