chr5-149008987-AG-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_024577.4(SH3TC2):c.3341del(p.Pro1114LeufsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
SH3TC2
NM_024577.4 frameshift
NM_024577.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.17
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 5-149008987-AG-A is Pathogenic according to our data. Variant chr5-149008987-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 21699.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-149008987-AG-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SH3TC2 | NM_024577.4 | c.3341del | p.Pro1114LeufsTer2 | frameshift_variant | 15/17 | ENST00000515425.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SH3TC2 | ENST00000515425.6 | c.3341del | p.Pro1114LeufsTer2 | frameshift_variant | 15/17 | 1 | NM_024577.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461880Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727242
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30
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727242
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease type 4C Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with SH3TC2 related disorder (ClinVar ID: VCV000021699 / PMID: 14574644). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at