rs146686472

chr4-153295620-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_015271.5(TRIM2):c.1094C>G(p.Thr365Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00019 in 1,613,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T365P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: TRIM2 NM_015271.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.00

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TRIM2
• BP4: Computational evidence support a benign effect (MetaRNN=0.06376022).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIM2	NM_015271.5	c.1094C>G	p.Thr365Ser	missense_variant	6/12	ENST00000338700.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIM2	ENST00000338700.10	c.1094C>G	p.Thr365Ser	missense_variant	6/12	1	NM_015271.5

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000211 AC: 53 AN: 250982 Hom.: 0 AF XY: 0.000243 AC XY: 33 AN XY: 135758

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000370

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000178 AC: 260 AN: 1461816 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 127 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000221

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74268

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000246 Hom.: 0

Bravo AF: 0.000310

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000709

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 22, 2018	The TRIM2 c.1013C>G; p.Thr338Ser variant (rs146686472), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with a non-Finnish European population frequency of 0.04% (identified on 45 out of 126,416 chromosomes) and is classified as a variant of unknown significance in ClinVar (ID: 444644). The threonine at position 338 is moderately conserved, considering 12 species, and computational analyses of the effects of the p.Thr338Ser variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Thr338Ser variant cannot be determined with certainty. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2022

The c.1094C>G (p.T365S) alteration is located in exon 6 (coding exon 6) of the TRIM2 gene. This alteration results from a C to G substitution at nucleotide position 1094, causing the threonine (T) at amino acid position 365 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease type 2R Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2023

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 338 of the TRIM2 protein (p.Thr338Ser). This variant is present in population databases (rs146686472, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with TRIM2-related conditions. ClinVar contains an entry for this variant (Variation ID: 444644). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.19	T;T;.
Eigen	Benign	0.0062
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.064	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N;.;.
MutationTaster	Benign	0.56	N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.26	N;.;N
REVEL	Benign	0.074
Sift	Benign	0.043	D;.;D
Sift4G	Benign	0.14	T;D;T
Polyphen		0.0	B;.;.
Vest4		0.11
MutPred		0.44		Gain of disorder (P = 0.1214);Gain of disorder (P = 0.1214);.;
MVP		0.12
MPC		0.70
ClinPred		0.030	T
GERP RS		5.5
Varity_R		0.15
gMVP		0.46

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: rs146686472; hg19: chr4-154216772;