rs772378888
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_024577.4(SH3TC2):āc.200A>Gā(p.Asn67Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.0000014 ( 0 hom. )
Consequence
SH3TC2
NM_024577.4 missense
NM_024577.4 missense
Scores
12
7
Clinical Significance
Conservation
PhyloP100: 4.47
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 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SH3TC2 | NM_024577.4 | c.200A>G | p.Asn67Ser | missense_variant | 3/17 | ENST00000515425.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SH3TC2 | ENST00000515425.6 | c.200A>G | p.Asn67Ser | missense_variant | 3/17 | 1 | NM_024577.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251460Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135902
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461862Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727234
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 10, 2022 | The p.N67S variant (also known as c.200A>G), located in coding exon 3 of the SH3TC2 gene, results from an A to G substitution at nucleotide position 200. The asparagine at codon 67 is replaced by serine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Charcot-Marie-Tooth disease type 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2019 | 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with SH3TC2-related disease. This variant is present in population databases (rs772378888, ExAC 0.001%). This sequence change replaces asparagine with serine at codon 67 of the SH3TC2 protein (p.Asn67Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Gain of phosphorylation at N67 (P = 0.0339);Gain of phosphorylation at N67 (P = 0.0339);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at