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GeneBe

rs17722227

chr5-149028382-C-T

Variant summary

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

The NM_024577.4(SH3TC2):c.1350G>A(p.Pro450=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,614,122 control chromosomes in the GnomAD database, including 2,295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 296 hom., cov: 32)
Exomes 𝑓: 0.018 ( 1999 hom. )

Consequence

SH3TC2
NM_024577.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.20
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
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.77).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 5-149028382-C-T is Benign according to our data. Variant chr5-149028382-C-T is described in ClinVar as [Benign]. Clinvar id is 139101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149028382-C-T is described in Lovd as [Benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-2.2 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SH3TC2NM_024577.4 linkuse as main transcriptc.1350G>A p.Pro450= synonymous_variant 11/17 ENST00000515425.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SH3TC2ENST00000515425.6 linkuse as main transcriptc.1350G>A p.Pro450= synonymous_variant 11/171 NM_024577.4 P2Q8TF17-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0258
AC:
3921
AN:
152180
Hom.:
293
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00702
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.150
Gnomad ASJ
AF:
0.00692
Gnomad EAS
AF:
0.103
Gnomad SAS
AF:
0.0583
Gnomad FIN
AF:
0.000942
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.00614
Gnomad OTH
AF:
0.0301
GnomAD3 exomes
AF:
0.0550
AC:
13794
AN:
251022
Hom.:
1583
AF XY:
0.0471
AC XY:
6396
AN XY:
135754
show subpopulations
Gnomad AFR exome
AF:
0.00659
Gnomad AMR exome
AF:
0.268
Gnomad ASJ exome
AF:
0.00764
Gnomad EAS exome
AF:
0.0973
Gnomad SAS exome
AF:
0.0533
Gnomad FIN exome
AF:
0.00111
Gnomad NFE exome
AF:
0.00592
Gnomad OTH exome
AF:
0.0351
GnomAD4 exome
AF:
0.0178
AC:
26032
AN:
1461824
Hom.:
1999
Cov.:
78
AF XY:
0.0177
AC XY:
12858
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.00499
Gnomad4 AMR exome
AF:
0.252
Gnomad4 ASJ exome
AF:
0.00708
Gnomad4 EAS exome
AF:
0.0768
Gnomad4 SAS exome
AF:
0.0500
Gnomad4 FIN exome
AF:
0.00122
Gnomad4 NFE exome
AF:
0.00498
Gnomad4 OTH exome
AF:
0.0233
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0258
AC:
3932
AN:
152298
Hom.:
296
Cov.:
32
AF XY:
0.0296
AC XY:
2205
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.00700
Gnomad4 AMR
AF:
0.151
Gnomad4 ASJ
AF:
0.00692
Gnomad4 EAS
AF:
0.102
Gnomad4 SAS
AF:
0.0581
Gnomad4 FIN
AF:
0.000942
Gnomad4 NFE
AF:
0.00615
Gnomad4 OTH
AF:
0.0307
Alfa
AF:
0.0172
Hom.:
243
Bravo
AF:
0.0373
Asia WGS
AF:
0.0970
AC:
335
AN:
3478

ClinVar

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

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxFeb 20, 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. -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 05, 2015- -
Charcot-Marie-Tooth disease Benign:1
Benign, criteria provided, single submitterclinical testingMolecular Genetics Laboratory, London Health Sciences Centre-- -
Charcot-Marie-Tooth disease type 4C Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 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. -
Susceptibility to mononeuropathy of the median nerve, mild Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 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 testingInvitaeJan 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.77
Cadd
Benign
1.2
Dann
Benign
0.49

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs17722227; hg19: chr5-148407945; COSMIC: COSV60463770; COSMIC: COSV60463770; API