9-35684736-T-C
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate
The NM_003289.4(TPM2):āc.635A>Gā(p.Asp212Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 32)
Exomes š: 0.0000021 ( 0 hom. )
Consequence
TPM2
NM_003289.4 missense
NM_003289.4 missense
Scores
7
8
3
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 7 ACMG points.
PM1
In a coiled_coil_region (size 283) in uniprot entity TPM2_HUMAN there are 37 pathogenic changes around while only 3 benign (93%) in NM_003289.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TPM2. . Gene score misZ 2.1346 (greater than the threshold 3.09). Trascript score misZ 3.2995 (greater than threshold 3.09). GenCC has associacion of gene with cap myopathy, typical nemaline myopathy, digitotalar dysmorphism, congenital fiber-type disproportion myopathy, childhood-onset nemaline myopathy, congenital myopathy 23, Sheldon-hall syndrome, arthrogryposis, distal, type 1A, TPM2-related myopathy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.864
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TPM2 | NM_003289.4 | c.635A>G | p.Asp212Gly | missense_variant | 6/9 | ENST00000645482.3 | NP_003280.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TPM2 | ENST00000645482.3 | c.635A>G | p.Asp212Gly | missense_variant | 6/9 | NM_003289.4 | ENSP00000496494.2 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152012Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251488Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135920
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727240
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 152012Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74272
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Arthrogryposis, distal, type 1A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 08, 2019 | In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TPM2-related disease. This sequence change replaces aspartic acid with glycine at codon 212 of the TPM2 protein (p.Asp212Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;.;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
.;M;M;.
PROVEAN
Uncertain
D;.;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.;D;.
Sift4G
Benign
T;.;T;T
Polyphen
0.0010
.;B;B;.
Vest4
MutPred
Loss of stability (P = 0.0209);Loss of stability (P = 0.0209);Loss of stability (P = 0.0209);.;
MVP
ClinPred
D
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at