9-35683177-A-AT
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_003289.4(TPM2):c.836dupA(p.Asn279fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Consequence
TPM2
NM_003289.4 frameshift
NM_003289.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.01
Genes affected
TPM2 (HGNC:12011): (tropomyosin 2) This gene encodes beta-tropomyosin, a member of the actin filament binding protein family, and mainly expressed in slow, type 1 muscle fibers. Mutations in this gene can alter the expression of other sarcomeric tropomyosin proteins, and cause cap disease, nemaline myopathy and distal arthrogryposis syndromes. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0222 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-35683177-A-AT is Pathogenic according to our data. Variant chr9-35683177-A-AT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2634361.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TPM2 | NM_003289.4 | c.836dupA | p.Asn279fs | frameshift_variant | 9/9 | ENST00000645482.3 | NP_003280.2 | |
TPM2 | NM_001301227.2 | c.836dupA | p.Asn279fs | frameshift_variant | 9/9 | NP_001288156.1 | ||
TPM2 | NM_001301226.2 | c.773-1015dupA | intron_variant | NP_001288155.1 | ||||
TPM2 | NM_213674.1 | c.773-1015dupA | intron_variant | NP_998839.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TPM2 | ENST00000645482.3 | c.836dupA | p.Asn279fs | frameshift_variant | 9/9 | NM_003289.4 | ENSP00000496494.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
TPM2-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 31, 2023 | The TPM2 c.836dupA variant is predicted to result in a frameshift and premature protein termination (p.Asn279Lysfs*2). This variant occurs in the last exon of the TPM2 gene and likely does not result in nonsense-mediated decay and only shortens the protein by five amino acids. To our knowledge, this variant has not been reported in the literature or public databases, indicating it is rare (http://gnomad.broadinstitute.org). At PreventionGenetics, we have observed the c.836dupA in an additional patient with features consistent with a TPM2-related disorder (internal data). We interpret this variant as likely pathogenic. - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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Calibrated prediction
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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
Publications
No publications associated with this variant yet.