5-149026635-C-T

Variant names:

• chr5-149026635-C-T
• rs140307699
• NM_024577.4:c.2990G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_024577.4(SH3TC2):​c.2990G>A​(p.Arg997Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,614,184 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.00049 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: SH3TC2 NM_024577.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 2.91

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

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022671163).
• BP6: Variant 5-149026635-C-T is Benign according to our data. Variant chr5-149026635-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241504.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000492 (75/152296) while in subpopulation AMR AF= 0.00268 (41/15304). AF 95% confidence interval is 0.00203. There are 1 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3TC2	NM_024577.4	c.2990G>A	p.Arg997Gln	missense_variant	Exon 12 of 17	ENST00000515425.6	NP_078853.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3TC2	ENST00000515425.6	c.2990G>A	p.Arg997Gln	missense_variant	Exon 12 of 17	1	NM_024577.4	ENSP00000423660.1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152178 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000358 AC: 90 AN: 251482 Hom.: 0 AF XY: 0.000346 AC XY: 47 AN XY: 135916

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000259 AC: 378 AN: 1461888 Hom.: 1 Cov.: 30 AF XY: 0.000257 AC XY: 187 AN XY: 727242

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.000842

Gnomad4 EAS exome AF: 0.000327

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000176

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000492 AC: 75 AN: 152296 Hom.: 1 Cov.: 33 AF XY: 0.000550 AC XY: 41 AN XY: 74484

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000366 Hom.: 0

Bravo AF: 0.000850

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000362 AC: 44

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SH3TC2: BP4 -

Feb 12, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 28, 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 disagree on the variant's effect on normal protein function. -

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

Feb 21, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Inborn genetic diseases Uncertain:1

Oct 05, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R997Q variant (also known as c.2990G>A), located in coding exon 12 of the SH3TC2 gene, results from a G to A substitution at nucleotide position 2990. The arginine at codon 997 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 Benign:1

Oct 15, 2024

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 4 Benign:1

Jan 17, 2025

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	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.023	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.0	L;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.030	D;D
Polyphen		0.88	P;.
Vest4		0.37
MVP		0.76
MPC		0.083
ClinPred		0.018	T
GERP RS		4.4
Varity_R		0.15
gMVP		0.19

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: rs140307699; hg19: chr5-148406198;