rs17722227

Variant names:

• chr5-149028382-C-T
• rs17722227
• NM_024577.4:c.1350G>A

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.1350G>A​(p.Pro450Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,614,122 control chromosomes in the GnomAD database, including 2,295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (296 hom., cov: 32)
  • Exomes 𝑓: 0.018 (1999 hom.)
• Consequence: SH3TC2 NM_024577.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.20
• Publications: 7 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=-0.77).
• BP6: Variant 5-149028382-C-T is Benign according to our data. Variant chr5-149028382-C-T is described in ClinVar as Benign. ClinVar VariationId is 139101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.146 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.1350G>A	p.Pro450Pro	synonymous	Exon 11 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.1350G>A	p.Pro450Pro	synonymous	Exon 11 of 17	ENSP00000423660.1	Q8TF17-1
	SH3TC2	ENST00000512049.5	TSL:1	c.1329G>A	p.Pro443Pro	synonymous	Exon 11 of 17	ENSP00000421860.1	Q8TF17-5
	SH3TC2	ENST00000323829.9	TSL:1	n.*738G>A		non_coding_transcript_exon	Exon 12 of 18	ENSP00000313025.5	D6RA65

Frequencies

GnomAD3 genomes AF: 0.0258 AC: 3921 AN: 152180 Hom.: 293 Cov.: 32

Gnomad AFR AF: 0.00702

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.0583

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00614

Gnomad OTH AF: 0.0301

GnomAD2 exomes AF: 0.0550 AC: 13794 AN: 251022 AF XY: 0.0471

Gnomad AFR exome AF: 0.00659

Gnomad AMR exome AF: 0.268

Gnomad ASJ exome AF: 0.00764

Gnomad EAS exome AF: 0.0973

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00592

Gnomad OTH exome AF: 0.0351

GnomAD4 exome AF: 0.0178 AC: 26032 AN: 1461824 Hom.: 1999 Cov.: 78 AF XY: 0.0177 AC XY: 12858 AN XY: 727224

African (AFR) AF: 0.00499 AC: 167 AN: 33480

American (AMR) AF: 0.252 AC: 11258 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00708 AC: 185 AN: 26136

East Asian (EAS) AF: 0.0768 AC: 3050 AN: 39700

South Asian (SAS) AF: 0.0500 AC: 4316 AN: 86256

European-Finnish (FIN) AF: 0.00122 AC: 65 AN: 53354

Middle Eastern (MID) AF: 0.00763 AC: 44 AN: 5768

European-Non Finnish (NFE) AF: 0.00498 AC: 5537 AN: 1112012

Other (OTH) AF: 0.0233 AC: 1410 AN: 60396

GnomAD4 genome AF: 0.0258 AC: 3932 AN: 152298 Hom.: 296 Cov.: 32 AF XY: 0.0296 AC XY: 2205 AN XY: 74468

African (AFR) AF: 0.00700 AC: 291 AN: 41572

American (AMR) AF: 0.151 AC: 2312 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3470

East Asian (EAS) AF: 0.102 AC: 530 AN: 5180

South Asian (SAS) AF: 0.0581 AC: 280 AN: 4818

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00615 AC: 418 AN: 68018

Other (OTH) AF: 0.0307 AC: 65 AN: 2116

Alfa AF: 0.0195 Hom.: 326

Bravo AF: 0.0373

Asia WGS AF: 0.0970 AC: 335 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	Charcot-Marie-Tooth disease type 4C (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	-0.77
CADD	Benign	1.2
DANN	Benign	0.49
PhyloP100		-2.2
Mutation Taster		=299/1	polymorphism (auto)

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: rs17722227; hg19: chr5-148407945; COSMIC: COSV60463770; COSMIC: COSV60463770;