GeneBe

rs6871030

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000515425.6(SH3TC2):ā€‹c.3594A>Gā€‹(p.Pro1198=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.044 in 1,613,864 control chromosomes in the GnomAD database, including 5,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…). Synonymous variant affecting the same amino acid position (i.e. P1198P) has been classified as Benign.

Frequency

Genomes: š‘“ 0.11 ( 1922 hom., cov: 31)
Exomes š‘“: 0.037 ( 3901 hom. )

Consequence

SH3TC2
ENST00000515425.6 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.87
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP6
Variant 5-149006962-T-C is Benign according to our data. Variant chr5-149006962-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 139102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149006962-T-C is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-1.87 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SH3TC2NM_024577.4 linkuse as main transcriptc.3594A>G p.Pro1198= synonymous_variant 16/17 ENST00000515425.6 NP_078853.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SH3TC2ENST00000515425.6 linkuse as main transcriptc.3594A>G p.Pro1198= synonymous_variant 16/171 NM_024577.4 ENSP00000423660 P2Q8TF17-1

Frequencies

GnomAD3 genomes
AF:
0.109
AC:
16577
AN:
151890
Hom.:
1910
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.269
Gnomad AMI
AF:
0.0176
Gnomad AMR
AF:
0.193
Gnomad ASJ
AF:
0.0337
Gnomad EAS
AF:
0.104
Gnomad SAS
AF:
0.0571
Gnomad FIN
AF:
0.00265
Gnomad MID
AF:
0.0538
Gnomad NFE
AF:
0.0195
Gnomad OTH
AF:
0.0978
GnomAD3 exomes
AF:
0.0839
AC:
21087
AN:
251460
Hom.:
2430
AF XY:
0.0706
AC XY:
9589
AN XY:
135896
show subpopulations
Gnomad AFR exome
AF:
0.277
Gnomad AMR exome
AF:
0.293
Gnomad ASJ exome
AF:
0.0311
Gnomad EAS exome
AF:
0.102
Gnomad SAS exome
AF:
0.0529
Gnomad FIN exome
AF:
0.00277
Gnomad NFE exome
AF:
0.0197
Gnomad OTH exome
AF:
0.0564
GnomAD4 exome
AF:
0.0372
AC:
54419
AN:
1461856
Hom.:
3901
Cov.:
46
AF XY:
0.0356
AC XY:
25922
AN XY:
727230
show subpopulations
Gnomad4 AFR exome
AF:
0.279
Gnomad4 AMR exome
AF:
0.279
Gnomad4 ASJ exome
AF:
0.0319
Gnomad4 EAS exome
AF:
0.0789
Gnomad4 SAS exome
AF:
0.0500
Gnomad4 FIN exome
AF:
0.00337
Gnomad4 NFE exome
AF:
0.0187
Gnomad4 OTH exome
AF:
0.0531
GnomAD4 genome
AF:
0.109
AC:
16631
AN:
152008
Hom.:
1922
Cov.:
31
AF XY:
0.110
AC XY:
8169
AN XY:
74282
show subpopulations
Gnomad4 AFR
AF:
0.269
Gnomad4 AMR
AF:
0.193
Gnomad4 ASJ
AF:
0.0337
Gnomad4 EAS
AF:
0.104
Gnomad4 SAS
AF:
0.0571
Gnomad4 FIN
AF:
0.00265
Gnomad4 NFE
AF:
0.0194
Gnomad4 OTH
AF:
0.0982
Alfa
AF:
0.0220
Hom.:
1235
EpiCase
AF:
0.0235
EpiControl
AF:
0.0203

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease Benign:1
Benign, criteria provided, single submitterclinical testingMolecular Genetics Laboratory, London Health Sciences Centre-- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxJan 28, 2014This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Charcot-Marie-Tooth disease type 4C Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 11, 2019This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Susceptibility to mononeuropathy of the median nerve, mild Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Charcot-Marie-Tooth disease type 4 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.80
CADD
Benign
4.3
DANN
Benign
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs6871030; hg19: chr5-148386525; API