5-149027150-C-T

Variant names:

• chr5-149027150-C-T
• rs142971473
• NM_024577.4:c.2582G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024577.4(SH3TC2):​c.2582G>A​(p.Arg861Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000206 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R861W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: SH3TC2 NM_024577.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: -0.199

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.110637575).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3TC2	NM_024577.4	c.2582G>A	p.Arg861Gln	missense_variant	Exon 11 of 17	ENST00000515425.6	NP_078853.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3TC2	ENST00000515425.6	c.2582G>A	p.Arg861Gln	missense_variant	Exon 11 of 17	1	NM_024577.4	ENSP00000423660.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000115 AC: 29 AN: 251220 AF XY: 0.000125

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000211 AC: 309 AN: 1461848 Hom.: 0 Cov.: 32 AF XY: 0.000213 AC XY: 155 AN XY: 727222

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000256 AC: 285 AN: 1112000

Other (OTH) AF: 0.000232 AC: 14 AN: 60394

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74466

African (AFR) AF: 0.0000241 AC: 1 AN: 41564

American (AMR) AF: 0.000458 AC: 7 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000258 Hom.: 0

Bravo AF: 0.000162

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Feb 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 24, 2023

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Available 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. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease Uncertain:1

-

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 4C Uncertain:1

Oct 30, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Mar 04, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R861Q variant (also known as c.2582G>A), located in coding exon 11 of the SH3TC2 gene, results from a G to A substitution at nucleotide position 2582. The arginine at codon 861 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well 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. -

Charcot-Marie-Tooth disease type 4C;C3150596:Susceptibility to mononeuropathy of the median nerve, mild Uncertain:1

Feb 18, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Charcot-Marie-Tooth disease type 4 Benign:1

Oct 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Uncertain	-0.021	T
MutationAssessor	Benign	1.7	L;.
PhyloP100		-0.20
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.27
Sift	Benign	0.18	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.88	P;.
Vest4		0.12
MVP		0.88
MPC		0.045
ClinPred		0.056	T
GERP RS		2.3
Varity_R		0.078
gMVP		0.060
Mutation Taster		=98/2	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

Publications

LitVar

Other links and lift over

dbSNP: rs142971473; hg19: chr5-148406713; COSMIC: COSV60467851; COSMIC: COSV60467851;