rs2234258

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PVS1_StrongBP6_Very_StrongBS1BS2

The ENST00000338469.3(TREM2):c.572G>A(p.Trp191*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,614,028 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 20 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 19 hom. )

Consequence

TREM2
ENST00000338469.3 stop_gained

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.72

Publications

23 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 -12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.133 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

BP6

Variant 6-41158691-C-T is Benign according to our data. Variant chr6-41158691-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0103 (1575/152262) while in subpopulation AFR AF = 0.0349 (1451/41544). AF 95% confidence interval is 0.0334. There are 20 homozygotes in GnomAd4. There are 724 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREM2	NM_018965.4 link	c.*73G>A		3_prime_UTR_variant	Exon 5 of 5	ENST00000373113.8	NP_061838.1	Q9NZC2-1Q5TCX1
TREM2	NM_001271821.2 link	c.572G>A	p.Trp191*	stop_gained	Exon 4 of 4		NP_001258750.1	Q9NZC2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TREM2	ENST00000373113.8 link	c.*73G>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_018965.4	ENSP00000362205.3		Q9NZC2-1

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1579

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0351

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00765

GnomAD2 exomes

AF:

0.00306

AC:

768

AN:

250988

AF XY:

0.00243

show subpopulations

Gnomad AFR exome

AF:

0.0387

Gnomad AMR exome

AF:

0.00278

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00114

AC:

1661

AN:

1461766

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

738

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.0331

AC:

1109

AN:

33476

American (AMR)

AF:

0.00300

AC:

134

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00225

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000228

AC:

253

AN:

1111958

Other (OTH)

AF:

0.00240

AC:

145

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

110

221

331

442

552

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.0103

AC:

1575

AN:

152262

Hom.:

Cov.:

AF XY:

0.00973

AC XY:

724

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0349

AC:

1451

AN:

41544

American (AMR)

AF:

0.00575

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68022

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

168

253

337

421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0118

Hom.:

Bravo

AF:

0.0131

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0311

AC:

ESP6500EA

AF:

0.000629

AC:

ExAC

AF:

0.00353

AC:

429

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Feb 04, 2016

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

Significance:Likely 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

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 03, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TREM2: BS1, BS2 -

not specified

Benign:1

Jun 26, 2018

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2

Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.11

(source)

DANN

Benign

0.61

Eigen

Benign

-0.95

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0056

PhyloP100

-1.7

Vest4

0.11

GERP RS

-2.9

Mutation Taster

=190/10

polymorphism

(source)

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

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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