6-41158917-A-G

Position:

chr6-41158917-A-G

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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 made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 356676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-41158917-A-G is described in Lovd as [Benign]. Variant chr6-41158917-A-G is described in Lovd as [Likely_benign].

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/exons	MANE	Protein	UniProt
TREM2	NM_018965.4 linkuse as main transcript	c.632T>C	p.Leu211Pro	missense_variant	4/5	ENST00000373113.8	NP_061838.1	Q9NZC2-1Q5TCX1
TREM2	NM_001271821.2 linkuse as main transcript	c.483-137T>C		intron_variant			NP_001258750.1	Q9NZC2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TREM2	ENST00000373113.8 linkuse as main transcript	c.632T>C	p.Leu211Pro	missense_variant	4/5	1	NM_018965.4	ENSP00000362205.3	Q9NZC2-1
TREM2	ENST00000373122 linkuse as main transcript	c.*3T>C		3_prime_UTR_variant	4/5	1		ENSP00000362214.4	Q9NZC2-3
TREM2	ENST00000338469.3 linkuse as main transcript	c.483-137T>C		intron_variant		1		ENSP00000342651.4	Q9NZC2-2
ENSG00000290034	ENST00000702590.1 linkuse as main transcript	n.364+3354A>G		intron_variant

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

GnomAD3 exomes

AF:

0.0176

AC:

4426

AN:

251454

Hom.:

236

AF XY:

0.0175

AC XY:

2377

AN XY:

135890

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 SAS exome

AF:

0.0584

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

Gnomad4 AFR exome

AF:

0.130

Gnomad4 AMR exome

AF:

0.0107

Gnomad4 ASJ exome

AF:

0.000957

Gnomad4 EAS exome

AF:

0.00355

Gnomad4 SAS exome

AF:

0.0561

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000893

Gnomad4 OTH exome

AF:

0.0141

GnomAD4 genome

AF:

0.0386

AC:

5879

AN:

152260

Hom.:

339

Cov.:

AF XY:

0.0383

AC XY:

2850

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.124

Gnomad4 AMR

AF:

0.0195

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00251

Gnomad4 SAS

AF:

0.0549

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00104

Gnomad4 OTH

AF:

0.0232

Alfa

AF:

0.00936

Hom.:

144

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2020	This variant is associated with the following publications: (PMID: 30917570, 25886450) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 22, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

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

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

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

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