chr6-41161469-C-T

Position:

chr6-41161469-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018965.4(TREM2):c.185G>A(p.Arg62His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00893 in 1,614,252 control chromosomes in the GnomAD database, including 88 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R62C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0071 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0091 ( 79 hom. )

Consequence

TREM2
NM_018965.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.342

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=0.0074675083).

BP6

Variant 6-41161469-C-T is Benign according to our data. Variant chr6-41161469-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-41161469-C-T is described in Lovd as [Benign]. Variant chr6-41161469-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00708 (1079/152362) while in subpopulation NFE AF= 0.0107 (731/68036). AF 95% confidence interval is 0.0101. There are 9 homozygotes in gnomad4. There are 482 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TREM2	NM_018965.4 linkuse as main transcript	c.185G>A	p.Arg62His	missense_variant	2/5	ENST00000373113.8	NP_061838.1	Q9NZC2-1Q5TCX1
TREM2	NM_001271821.2 linkuse as main transcript	c.185G>A	p.Arg62His	missense_variant	2/4		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.185G>A	p.Arg62His	missense_variant	2/5	1	NM_018965.4	ENSP00000362205.3	Q9NZC2-1
TREM2	ENST00000373122.8 linkuse as main transcript	c.185G>A	p.Arg62His	missense_variant	2/5	1		ENSP00000362214.4	Q9NZC2-3
TREM2	ENST00000338469.3 linkuse as main transcript	c.185G>A	p.Arg62His	missense_variant	2/4	1		ENSP00000342651.4	Q9NZC2-2
ENSG00000290034	ENST00000702590.1 linkuse as main transcript	n.364+5906C>T		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.00709

AC:

1079

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00909

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00706

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.00573

GnomAD3 exomes

AF:

0.00763

AC:

1917

AN:

251258

Hom.:

AF XY:

0.00720

AC XY:

978

AN XY:

135794

show subpopulations

Gnomad AFR exome

AF:

0.00215

Gnomad AMR exome

AF:

0.00706

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00363

Gnomad FIN exome

AF:

0.00804

Gnomad NFE exome

AF:

0.0112

Gnomad OTH exome

AF:

0.00962

GnomAD4 exome

AF:

0.00912

AC:

13332

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00888

AC XY:

6459

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00182

Gnomad4 AMR exome

AF:

0.00738

Gnomad4 ASJ exome

AF:

0.00291

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00327

Gnomad4 FIN exome

AF:

0.00711

Gnomad4 NFE exome

AF:

0.0105

Gnomad4 OTH exome

AF:

0.00791

GnomAD4 genome

AF:

0.00708

AC:

1079

AN:

152362

Hom.:

Cov.:

AF XY:

0.00647

AC XY:

482

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00209

Gnomad4 AMR

AF:

0.00908

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00352

Gnomad4 FIN

AF:

0.00706

Gnomad4 NFE

AF:

0.0107

Gnomad4 OTH

AF:

0.00567

Alfa

AF:

0.00958

Hom.:

Bravo

AF:

0.00687

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0103

AC:

ExAC

AF:

0.00825

AC:

1002

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0104

EpiControl

AF:

0.00859

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2020	This variant is associated with the following publications: (PMID: 29723869, 30530974, 28714976, 26754641, 29557178, 28430856, 29177109, 26021840, 24899047, 25886450) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TREM2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 25, 2017	- -

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Sep 14, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.086

.;T;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.78

T;T;T

MetaRNN

Benign

0.0075

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.61

N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.13

N;N;N

REVEL

Benign

0.039

Sift

Benign

0.24

T;T;T

Sift4G

Benign

0.36

T;T;T

Polyphen

0.14

B;B;B

Vest4

0.11

MVP

0.49

MPC

0.19

ClinPred

0.0027

GERP RS

-0.21

Varity_R

0.10

gMVP

0.38

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