rs763331671
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_024577.4(SH3TC2):c.2989C>T(p.Arg997Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
SH3TC2
NM_024577.4 missense
NM_024577.4 missense
Scores
2
13
4
Clinical Significance
Conservation
PhyloP100: 3.15
Genes affected
SH3TC2 (HGNC:29427): (SH3 domain and tetratricopeptide repeats 2) This gene encodes a protein with two N-terminal Src homology 3 (SH3) domains and 10 tetratricopeptide repeat (TPR) motifs, and is a member of a small gene family. The gene product has been proposed to be an adapter or docking molecule. Mutations in this gene result in autosomal recessive Charcot-Marie-Tooth disease type 4C, a childhood-onset neurodegenerative disease characterized by demyelination of motor and sensory neurons. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 5-149026636-G-A is Benign according to our data. Variant chr5-149026636-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 578843.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SH3TC2 | NM_024577.4 | c.2989C>T | p.Arg997Trp | missense_variant | 12/17 | ENST00000515425.6 | NP_078853.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SH3TC2 | ENST00000515425.6 | c.2989C>T | p.Arg997Trp | missense_variant | 12/17 | 1 | NM_024577.4 | ENSP00000423660.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152124Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251470Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135906
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GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461890Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11AN XY: 727246
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152124Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74310
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 10, 2024 | Variant summary: SH3TC2 c.2989C>T (p.Arg997Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251470 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SH3TC2 causing Charcot-Marie Disease Type 4C, allowing no conclusion about variant significance. c.2989C>T has been reported in the literature in an individual affected with Charcot-Marie Disease, however the variant co-occurred with a pathogenic variant (PMP22 c.215C>T, p.Ser72Leu), providing supporting evidence for a benign role (Choi_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 22730194). ClinVar contains an entry for this variant (Variation ID: 578843). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Charcot-Marie-Tooth disease type 4 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 13, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
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