chr5-149052214-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_024577.4(SH3TC2):c.79A>G(p.Thr27Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,613,062 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 8 hom. )

Consequence

SH3TC2
NM_024577.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:7

Conservation

PhyloP100: -0.120

Publications

5 publications found

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]

SH3TC2 Gene-Disease associations (from GenCC):

autosomal recessive hereditary demyelinating motor and sensory neuropathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease type 4C
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
susceptibility to mononeuropathy of the median nerve, mild
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

SH3TC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00543043).

BP6

Variant 5-149052214-T-C is Benign according to our data. Variant chr5-149052214-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220296.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00127 (193/152326) while in subpopulation NFE AF = 0.00182 (124/68024). AF 95% confidence interval is 0.00156. There are 1 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3TC2	NM_024577.4 link	c.79A>G	p.Thr27Ala	missense_variant	Exon 2 of 17	ENST00000515425.6	NP_078853.2	Q8TF17-1A0A514TP98

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3TC2	ENST00000515425.6 link	c.79A>G	p.Thr27Ala	missense_variant	Exon 2 of 17	1	NM_024577.4	ENSP00000423660.1		Q8TF17-1

Frequencies

GnomAD3 genomes

AF:

0.00127

AC:

193

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00182

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00133

AC:

335

AN:

251358

AF XY:

0.00132

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00203

Gnomad NFE exome

AF:

0.00200

Gnomad OTH exome

AF:

0.000980

GnomAD4 exome

AF:

0.00178

AC:

2604

AN:

1460736

Hom.:

Cov.:

AF XY:

0.00174

AC XY:

1267

AN XY:

726784

show subpopulations

African (AFR)

AF:

0.000598

AC:

AN:

33444

American (AMR)

AF:

0.000179

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26120

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39666

South Asian (SAS)

AF:

0.00162

AC:

140

AN:

86232

European-Finnish (FIN)

AF:

0.00240

AC:

128

AN:

53374

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00202

AC:

2248

AN:

1111068

Other (OTH)

AF:

0.000895

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

117

234

351

468

585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00127

AC:

193

AN:

152326

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.000698

AC:

AN:

41570

American (AMR)

AF:

0.00111

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00182

AC:

124

AN:

68024

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00159

Hom.:

Bravo

AF:

0.00110

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00131

AC:

159

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00158

EpiControl

AF:

0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

May 05, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 18, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26392352, 21291453, 32376792) -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SH3TC2: BP4, BS2 -

Nov 18, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease

Uncertain:2

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inherited Neuropathy Consortium

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Uncertain:1Benign:1

Jul 18, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 29, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SH3TC2 c.79A>G (p.Thr27Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 251358 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in SH3TC2 causing Charcot-Marie-Tooth disease type 4C, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.79A>G in individuals affected with Charcot-Marie-Tooth disease type 4C and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 220296). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Charcot-Marie-Tooth disease type 4C

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Susceptibility to mononeuropathy of the median nerve, mild

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Inborn genetic diseases

Benign:1

Jan 02, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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. -

SH3TC2-related disorder

Benign:1

Feb 07, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Charcot-Marie-Tooth disease type 4

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.021

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.054

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.39

T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.0054

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.63

N;N

PhyloP100

-0.12

PrimateAI

Benign

0.26

PROVEAN

Benign

0.060

N;N

REVEL

Benign

0.11

Sift

Benign

0.59

T;T

Sift4G

Benign

0.72

T;T

Polyphen

0.0

B;.

Vest4

0.071

MVP

0.40

MPC

0.039

ClinPred

0.00078

GERP RS

-3.5

Varity_R

0.028

gMVP

0.12

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over