rs1399431033

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024577.4(SH3TC2):ā€‹c.82G>Cā€‹(p.Val28Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

SH3TC2
NM_024577.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -2.58
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.057418495).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SH3TC2NM_024577.4 linkuse as main transcriptc.82G>C p.Val28Leu missense_variant 2/17 ENST00000515425.6 NP_078853.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SH3TC2ENST00000515425.6 linkuse as main transcriptc.82G>C p.Val28Leu missense_variant 2/171 NM_024577.4 ENSP00000423660 P2Q8TF17-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152158
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251376
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135856
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460958
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
726860
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152158
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000564
Hom.:
0
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 11, 2020The p.V28L variant (also known as c.82G>C), located in coding exon 2 of the SH3TC2 gene, results from a G to C substitution at nucleotide position 82. The valine at codon 28 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. 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. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsSep 26, 2022Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools predict that this variant is not damaging. -
Charcot-Marie-Tooth disease type 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 27, 2021This sequence change replaces valine with leucine at codon 28 of the SH3TC2 protein (p.Val28Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with SH3TC2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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
0.075
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
0.0030
DANN
Benign
0.70
DEOGEN2
Benign
0.065
T;.
Eigen
Benign
-2.0
Eigen_PC
Benign
-2.1
FATHMM_MKL
Benign
0.0076
N
LIST_S2
Benign
0.65
T;T
M_CAP
Benign
0.0092
T
MetaRNN
Benign
0.057
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N;N
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-0.62
N;N
REVEL
Benign
0.15
Sift
Benign
0.41
T;T
Sift4G
Benign
0.34
T;T
Polyphen
0.0
B;.
Vest4
0.063
MutPred
0.065
Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);
MVP
0.31
MPC
0.039
ClinPred
0.069
T
GERP RS
-11
Varity_R
0.032
gMVP
0.085

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1399431033; hg19: chr5-148431774; API