rs6871030

Variant names:

• chr5-149006962-T-C
• rs6871030
• NM_024577.4:c.3594A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-149006962-T-C
• chr5-149006962-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024577.4(SH3TC2):​c.3594A>G​(p.Pro1198Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.044 in 1,613,864 control chromosomes in the GnomAD database, including 5,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1198P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (1922 hom., cov: 31)
  • Exomes 𝑓: 0.037 (3901 hom.)
• Consequence: SH3TC2 NM_024577.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.87
• Publications: 22 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), Ambry Genetics, Orphanet
• susceptibility to mononeuropathy of the median nerve, mild

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 5-149006962-T-C is Benign according to our data. Variant chr5-149006962-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.87 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024577.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3TC2	NM_024577.4	MANE Select	c.3594A>G	p.Pro1198Pro	synonymous	Exon 16 of 17	NP_078853.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3TC2	ENST00000515425.6	TSL:1 MANE Select	c.3594A>G	p.Pro1198Pro	synonymous	Exon 16 of 17	ENSP00000423660.1	Q8TF17-1
	SH3TC2	ENST00000512049.5	TSL:1	c.3573A>G	p.Pro1191Pro	synonymous	Exon 16 of 17	ENSP00000421860.1	Q8TF17-5
	SH3TC2	ENST00000323829.9	TSL:1	n.*2982A>G		non_coding_transcript_exon	Exon 17 of 18	ENSP00000313025.5	D6RA65

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16577 AN: 151890 Hom.: 1910 Cov.: 31

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.0337

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.0571

Gnomad FIN AF: 0.00265

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0978

GnomAD2 exomes AF: 0.0839 AC: 21087 AN: 251460 AF XY: 0.0706

Gnomad AFR exome AF: 0.277

Gnomad AMR exome AF: 0.293

Gnomad ASJ exome AF: 0.0311

Gnomad EAS exome AF: 0.102

Gnomad FIN exome AF: 0.00277

Gnomad NFE exome AF: 0.0197

Gnomad OTH exome AF: 0.0564

GnomAD4 exome AF: 0.0372 AC: 54419 AN: 1461856 Hom.: 3901 Cov.: 46 AF XY: 0.0356 AC XY: 25922 AN XY: 727230

African (AFR) AF: 0.279 AC: 9341 AN: 33480

American (AMR) AF: 0.279 AC: 12459 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0319 AC: 834 AN: 26136

East Asian (EAS) AF: 0.0789 AC: 3134 AN: 39700

South Asian (SAS) AF: 0.0500 AC: 4314 AN: 86258

European-Finnish (FIN) AF: 0.00337 AC: 180 AN: 53420

Middle Eastern (MID) AF: 0.0317 AC: 183 AN: 5766

European-Non Finnish (NFE) AF: 0.0187 AC: 20767 AN: 1111978

Other (OTH) AF: 0.0531 AC: 3207 AN: 60394

GnomAD4 genome AF: 0.109 AC: 16631 AN: 152008 Hom.: 1922 Cov.: 31 AF XY: 0.110 AC XY: 8169 AN XY: 74282

African (AFR) AF: 0.269 AC: 11165 AN: 41460

American (AMR) AF: 0.193 AC: 2953 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0337 AC: 117 AN: 3468

East Asian (EAS) AF: 0.104 AC: 533 AN: 5142

South Asian (SAS) AF: 0.0571 AC: 275 AN: 4812

European-Finnish (FIN) AF: 0.00265 AC: 28 AN: 10578

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0194 AC: 1321 AN: 67954

Other (OTH) AF: 0.0982 AC: 207 AN: 2108

Alfa AF: 0.0220 Hom.: 1235

EpiCase AF: 0.0235

EpiControl AF: 0.0203

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	Charcot-Marie-Tooth disease type 4C (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Susceptibility to mononeuropathy of the median nerve, mild (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.3
DANN	Benign	0.70
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6871030; hg19: chr5-148386525;