rs1554002777

chr4-153324090-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_015271.5(TRIM2):c.1964C>A(p.Ala655Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRIM2 NM_015271.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.93

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TRIM2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIM2	NM_015271.5	c.1964C>A	p.Ala655Glu	missense_variant	10/12	ENST00000338700.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIM2	ENST00000338700.10	c.1964C>A	p.Ala655Glu	missense_variant	10/12	1	NM_015271.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 22, 2017

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with TRIM2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glutamic acid at codon 628 of the TRIM2 protein (p.Ala628Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.96	D;.
Vest4		0.86
MutPred		0.77		Gain of disorder (P = 0.0771);.;
MVP		0.59
MPC		1.4
ClinPred		0.97	D
GERP RS		6.0
Varity_R		0.60
gMVP		0.98

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: rs1554002777; hg19: chr4-154245242;