NM_024577.4:c.1194T>C

Variant names:

• chr5-149028538-A-G
• rs1432793
• NM_024577.4:c.1194T>C

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.1194T>C​(p.Gly398Gly) 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
• Publications: 19 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=-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 VariationId is 130296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.1194T>C	p.Gly398Gly	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.1194T>C	p.Gly398Gly	synonymous	Exon 11 of 17	ENSP00000423660.1	Q8TF17-1
	SH3TC2	ENST00000512049.5	TSL:1	c.1173T>C	p.Gly391Gly	synonymous	Exon 11 of 17	ENSP00000421860.1	Q8TF17-5
	SH3TC2	ENST00000323829.9	TSL:1	n.*582T>C		non_coding_transcript_exon	Exon 12 of 18	ENSP00000313025.5	D6RA65

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

GnomAD2 exomes AF: 0.439 AC: 109882 AN: 250196 AF XY: 0.445

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 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

African (AFR) AF: 0.575 AC: 19253 AN: 33478

American (AMR) AF: 0.316 AC: 14119 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 12529 AN: 26136

East Asian (EAS) AF: 0.286 AC: 11350 AN: 39696

South Asian (SAS) AF: 0.473 AC: 40830 AN: 86254

European-Finnish (FIN) AF: 0.546 AC: 29129 AN: 53364

Middle Eastern (MID) AF: 0.468 AC: 2700 AN: 5766

European-Non Finnish (NFE) AF: 0.451 AC: 501624 AN: 1111912

Other (OTH) AF: 0.451 AC: 27266 AN: 60394

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

African (AFR) AF: 0.572 AC: 23689 AN: 41448

American (AMR) AF: 0.371 AC: 5667 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1685 AN: 3470

East Asian (EAS) AF: 0.275 AC: 1411 AN: 5130

South Asian (SAS) AF: 0.475 AC: 2283 AN: 4810

European-Finnish (FIN) AF: 0.560 AC: 5915 AN: 10562

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.457 AC: 31048 AN: 67920

Other (OTH) AF: 0.466 AC: 984 AN: 2110

Alfa AF: 0.455 Hom.: 27594

Bravo AF: 0.468

Asia WGS AF: 0.361 AC: 1255 AN: 3478

EpiCase AF: 0.454

EpiControl AF: 0.451

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Charcot-Marie-Tooth disease type 4C (2)
-	-	2	Susceptibility to mononeuropathy of the median nerve, mild (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	3.7
DANN	Benign	0.50
PhyloP100		0.49
Mutation Taster		=100/0	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: rs1432793; hg19: chr5-148408101; COSMIC: COSV60463118; COSMIC: COSV60463118;