rs863224780

Variant names:

• chr5-149028329-GC-AA
• rs863224780
• NM_024577.4:c.1402_1403delGCinsTT

Your query was ambiguous. Multiple possible variants found:

• chr5-149028329-GC-AA
• chr5-149028329-GC-TT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_024577.4(SH3TC2):​c.1402_1403delGCinsTT​(p.Ala468Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.00361 in 1,020 alleles, including 3 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A468V) has been classified as Likely benign.

• Frequency: GnomAD MNV: 𝑓 0.0036 Genomes: not found (cov: 32)
• Consequence: SH3TC2 NM_024577.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:3
• Conservation: PhyloP100: 1.84
• Publications: 2 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 5-149028329-GC-AA is Benign according to our data. Variant chr5-149028329-GC-AA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216737.

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.1402_1403delGCinsTT	p.Ala468Phe	missense	N/A	NP_078853.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3TC2	ENST00000515425.6	TSL:1 MANE Select	c.1402_1403delGCinsTT	p.Ala468Phe	missense	N/A	ENSP00000423660.1	Q8TF17-1
	SH3TC2	ENST00000512049.5	TSL:1	c.1381_1382delGCinsTT	p.Ala461Phe	missense	N/A	ENSP00000421860.1	Q8TF17-5
	SH3TC2	ENST00000323829.9	TSL:1	n.*790_*791delGCinsTT		non_coding_transcript_exon	Exon 12 of 18	ENSP00000313025.5	D6RA65

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

GnomAD MNV AF: 0.00361 AC: 1020 Hom.: 3

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Charcot-Marie-Tooth disease (2)
-	-	2	not provided (2)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	1	-	Distal spinal muscular atrophy (1)
1	-	-	Hereditary spastic paraplegia (1)
-	1	-	Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs863224780; hg19: chr5-148407892;