rs1432793

Positions:

• chr5-149028538-A-G
• chr5-149028538-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024577.4(SH3TC2):​c.1194T>C​(p.Gly398=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 1,613,636 control chromosomes in the GnomAD database, including 169,019 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18147 hom., cov: 32)
  • Exomes 𝑓: 0.45 (150872 hom.)
• Consequence: SH3TC2 NM_024577.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.493

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 5-149028538-A-G is Benign according to our data. Variant chr5-149028538-A-G is described in ClinVar as [Benign]. Clinvar id is 130296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149028538-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.493 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3TC2	NM_024577.4	c.1194T>C	p.Gly398=	synonymous_variant	11/17	ENST00000515425.6	NP_078853.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3TC2	ENST00000515425.6	c.1194T>C	p.Gly398=	synonymous_variant	11/17	1	NM_024577.4	ENSP00000423660	P2

Frequencies

GnomAD3 genomes AF: 0.482 AC: 73208 AN: 151812 Hom.: 18138 Cov.: 32

Gnomad AFR AF: 0.572

Gnomad AMI AF: 0.498

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.477

Gnomad FIN AF: 0.560

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.465

GnomAD3 exomes AF: 0.439 AC: 109882 AN: 250196 Hom.: 25110 AF XY: 0.445 AC XY: 60324 AN XY: 135536

Gnomad AFR exome AF: 0.567

Gnomad AMR exome AF: 0.308

Gnomad ASJ exome AF: 0.487

Gnomad EAS exome AF: 0.272

Gnomad SAS exome AF: 0.473

Gnomad FIN exome AF: 0.554

Gnomad NFE exome AF: 0.453

Gnomad OTH exome AF: 0.443

GnomAD4 exome AF: 0.451 AC: 658800 AN: 1461706 Hom.: 150872 Cov.: 78 AF XY: 0.452 AC XY: 328390 AN XY: 727144

Gnomad4 AFR exome AF: 0.575

Gnomad4 AMR exome AF: 0.316

Gnomad4 ASJ exome AF: 0.479

Gnomad4 EAS exome AF: 0.286

Gnomad4 SAS exome AF: 0.473

Gnomad4 FIN exome AF: 0.546

Gnomad4 NFE exome AF: 0.451

Gnomad4 OTH exome AF: 0.451

GnomAD4 genome AF: 0.482 AC: 73257 AN: 151930 Hom.: 18147 Cov.: 32 AF XY: 0.486 AC XY: 36072 AN XY: 74270

Gnomad4 AFR AF: 0.572

Gnomad4 AMR AF: 0.371

Gnomad4 ASJ AF: 0.486

Gnomad4 EAS AF: 0.275

Gnomad4 SAS AF: 0.475

Gnomad4 FIN AF: 0.560

Gnomad4 NFE AF: 0.457

Gnomad4 OTH AF: 0.466

Alfa AF: 0.454 Hom.: 24565

Bravo AF: 0.468

Asia WGS AF: 0.361 AC: 1255 AN: 3478

EpiCase AF: 0.454

EpiControl AF: 0.451

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Charcot-Marie-Tooth disease type 4C Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Susceptibility to mononeuropathy of the median nerve, mild Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Charcot-Marie-Tooth disease type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	3.7
DANN	Benign	0.50

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: rs1432793; hg19: chr5-148408101; COSMIC: COSV60463118; COSMIC: COSV60463118;