4-153270426-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_015271.5(TRIM2):c.122G>A(p.Arg41His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,613,988 control chromosomes in the GnomAD database, including 6 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. R41C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (6 hom.)
• Consequence: TRIM2 NM_015271.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 9.88

Genes affected

TRIM2 (HGNC:15974): (tripartite motif containing 2) The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The protein localizes to cytoplasmic filaments. It plays a neuroprotective role and functions as an E3-ubiquitin ligase in proteasome-mediated degradation of target proteins. Mutations in this gene can cause early-onset axonal neuropathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TRIM2
• BP4: Computational evidence support a benign effect (MetaRNN=0.020416021).
• BP6: Variant 4-153270426-G-A is Benign according to our data. Variant chr4-153270426-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 474610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-153270426-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIM2	NM_015271.5	c.122G>A	p.Arg41His	missense_variant	2/12	ENST00000338700.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIM2	ENST00000338700.10	c.122G>A	p.Arg41His	missense_variant	2/12	1	NM_015271.5

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 236 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00185 AC: 466 AN: 251258 Hom.: 4 AF XY: 0.00180 AC XY: 244 AN XY: 135790

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00189

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00208

Gnomad NFE exome AF: 0.00282

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00185 AC: 2704 AN: 1461738 Hom.: 6 Cov.: 31 AF XY: 0.00175 AC XY: 1275 AN XY: 727180

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00223

Gnomad4 NFE exome AF: 0.00214

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00155 AC: 236 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.00150 AC XY: 112 AN XY: 74462

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.00231

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00174 Hom.: 0

Bravo AF: 0.00147

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00195 AC: 237

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00224

EpiControl AF: 0.00338

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TRIM2: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2020	- -

Charcot-Marie-Tooth disease type 2R Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 30, 2019	- -

TRIM2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 04, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.020
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;.;D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.020	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.13	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.8	N;N;.;N;.;.;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.027	D;D;.;D;.;.;.
Sift4G	Uncertain	0.036	D;D;D;D;D;T;D
Polyphen		1.0	D;D;.;.;.;.;.
Vest4		0.82, 0.77, 0.75, 0.79, 0.73
MVP		0.51
MPC		1.9
ClinPred		0.025	T
GERP RS		5.7
Varity_R		0.23
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs146705057; hg19: chr4-154191578; COSMIC: COSV105246118; COSMIC: COSV105246118;