rs150120234
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP2BS2
The NM_003289.4(TPM2):c.536C>T(p.Ser179Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S179S) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )
Consequence
TPM2
NM_003289.4 missense
NM_003289.4 missense
Scores
6
9
2
Clinical Significance
Conservation
PhyloP100: 10.0
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_benign. Variant got -1 ACMG points.
PM1
?
In a coiled_coil_region (size 283) in uniprot entity TPM2_HUMAN there are 63 pathogenic changes around while only 5 benign (93%) in NM_003289.4
PP2
?
Missense variant where missense usually causes diseases, TPM2
BS2
?
High AC in GnomAd4 at 25 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPM2 | NM_003289.4 | c.536C>T | p.Ser179Leu | missense_variant | 5/9 | ENST00000645482.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPM2 | ENST00000645482.3 | c.536C>T | p.Ser179Leu | missense_variant | 5/9 | NM_003289.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000164 AC: 25AN: 152144Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251354Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135874
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GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461886Hom.: 0 Cov.: 35 AF XY: 0.0000303 AC XY: 22AN XY: 727248
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GnomAD4 genome ? AF: 0.000164 AC: 25AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74312
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 09, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 02, 2017 | - - |
Arthrogryposis, distal, type 1A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 179 of the TPM2 protein (p.Ser179Leu). This variant is present in population databases (rs150120234, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with TPM2-related conditions. ClinVar contains an entry for this variant (Variation ID: 458724). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TPM2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;M;M;M;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;.;D;.;.
REVEL
Pathogenic
Sift
Uncertain
D;D;D;.;D;.;.
Sift4G
Benign
T;T;T;.;D;.;T
Polyphen
P;.;P;P;P;P;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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