6-41161469-C-T

Position:

• chr6-41161469-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.342

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]

ENSG00000290034 (HGNC:):

ACMG classification

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	c.185G>A	p.Arg62His	missense_variant	2/5	ENST00000373113.8	NP_061838.1
TREM2	NM_001271821.2	c.185G>A	p.Arg62His	missense_variant	2/4		NP_001258750.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00709 AC: 1079 AN: 152244 Hom.: 9 Cov.: 32

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.: 15 AF XY: 0.00720 AC XY: 978 AN XY: 135794

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.: 79 Cov.: 32 AF XY: 0.00888 AC XY: 6459 AN XY: 727244

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.: 9 Cov.: 32 AF XY: 0.00647 AC XY: 482 AN XY: 74506

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.: 16

Bravo AF: 0.00687

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0103 AC: 89

ExAC AF: 0.00825 AC: 1002

Asia WGS AF: 0.00144 AC: 5 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

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	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.086	.;T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.78	T;T;T
MetaRNN	Benign	0.0075	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.61	N;N;N
PrimateAI	Benign	0.24	T
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	T
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

Other links and lift over

dbSNP: rs143332484; hg19: chr6-41129207; COSMIC: COSV58295142;