rs759938444
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_015271.5(TRIM2):āc.659T>Cā(p.Leu220Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
TRIM2
NM_015271.5 missense
NM_015271.5 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 7.67
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 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, 0.873
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRIM2 | NM_015271.5 | c.659T>C | p.Leu220Ser | missense_variant | 5/12 | ENST00000338700.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRIM2 | ENST00000338700.10 | c.659T>C | p.Leu220Ser | missense_variant | 5/12 | 1 | NM_015271.5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152192Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251454Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135902
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461870Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727234
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74366
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease type 2R Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 02, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 193 of the TRIM2 protein (p.Leu193Ser). This variant is present in population databases (rs759938444, gnomAD 0.0009%). 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: 474612). 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 disruptive. 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;T;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;.;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
D;.;.;.
Vest4
MutPred
Gain of disorder (P = 0.0057);Gain of disorder (P = 0.0057);.;.;
MVP
MPC
2.2
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at