rs80227512

Variant names:

• chr5-149041502-G-A
• rs80227512
• NM_024577.4:c.645C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-149041502-G-A
• chr5-149041502-G-C
• chr5-149041502-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_024577.4(SH3TC2):​c.645C>T​(p.Ser215Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00908 in 1,614,160 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0065 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0093 (101 hom.)
• Consequence: SH3TC2 NM_024577.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -1.79
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-149041502-G-A is Benign according to our data. Variant chr5-149041502-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130301.
• BP7: Synonymous conserved (PhyloP=-1.79 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00651 (992/152302) while in subpopulation SAS AF = 0.0226 (109/4830). AF 95% confidence interval is 0.0191. There are 5 homozygotes in GnomAd4. There are 453 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3TC2	NM_024577.4	c.645C>T	p.Ser215Ser	synonymous_variant	Exon 6 of 17	ENST00000515425.6	NP_078853.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3TC2	ENST00000515425.6	c.645C>T	p.Ser215Ser	synonymous_variant	Exon 6 of 17	1	NM_024577.4	ENSP00000423660.1

Frequencies

GnomAD3 genomes AF: 0.00652 AC: 992 AN: 152184 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0225

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00935

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00907 AC: 2279 AN: 251280 AF XY: 0.0103

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00353

Gnomad ASJ exome AF: 0.0170

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00481

Gnomad NFE exome AF: 0.00990

Gnomad OTH exome AF: 0.00963

GnomAD4 exome AF: 0.00935 AC: 13667 AN: 1461858 Hom.: 101 Cov.: 31 AF XY: 0.00994 AC XY: 7225 AN XY: 727224

African (AFR) AF: 0.00143 AC: 48 AN: 33480

American (AMR) AF: 0.00387 AC: 173 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0145 AC: 379 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0220 AC: 1898 AN: 86256

European-Finnish (FIN) AF: 0.00539 AC: 288 AN: 53416

Middle Eastern (MID) AF: 0.0125 AC: 72 AN: 5748

European-Non Finnish (NFE) AF: 0.00925 AC: 10288 AN: 1112010

Other (OTH) AF: 0.00861 AC: 520 AN: 60390

GnomAD4 genome AF: 0.00651 AC: 992 AN: 152302 Hom.: 5 Cov.: 33 AF XY: 0.00608 AC XY: 453 AN XY: 74492

African (AFR) AF: 0.00176 AC: 73 AN: 41556

American (AMR) AF: 0.00418 AC: 64 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0226 AC: 109 AN: 4830

European-Finnish (FIN) AF: 0.00377 AC: 40 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00935 AC: 636 AN: 68020

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00655 Hom.: 4

Bravo AF: 0.00591

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.00998

EpiControl AF: 0.0116

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Mar 06, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease Benign:1

-

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

May 19, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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

Jul 11, 2019

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. -

Charcot-Marie-Tooth disease type 4 Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Susceptibility to mononeuropathy of the median nerve, mild Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.56
DANN	Benign	0.43
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs80227512; hg19: chr5-148421065; COSMIC: COSV60464760; COSMIC: COSV60464760;