9-35682160-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP2BP4_ModerateBS2

The NM_213674.1(TPM2):ā€‹c.776C>Gā€‹(p.Thr259Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000041 ( 0 hom. )

Consequence

TPM2
NM_213674.1 missense

Scores

3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.66
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1
In a coiled_coil_region (size 283) in uniprot entity TPM2_HUMAN there are 34 pathogenic changes around while only 2 benign (94%) in NM_213674.1
PP2
Missense variant in the TPM2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 19 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.1346 (below the threshold of 3.09). Trascript score misZ: 3.2245 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.20952818).
BS2
High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TPM2NM_001301226.2 linkc.776C>G p.Thr259Ser missense_variant Exon 9 of 9 NP_001288155.1 Q5TCU3V9HW25
TPM2NM_213674.1 linkc.776C>G p.Thr259Ser missense_variant Exon 9 of 9 NP_998839.1 P07951-2V9HW25

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TPM2ENST00000378292.9 linkc.776C>G p.Thr259Ser missense_variant Exon 9 of 9 1 ENSP00000367542.3 P07951-2
TPM2ENST00000329305.6 linkc.776C>G p.Thr259Ser missense_variant Exon 9 of 9 2 ENSP00000367541.1 Q5TCU3
TPM2ENST00000644325 linkc.*548C>G 3_prime_UTR_variant Exon 4 of 4 ENSP00000495075.1 A0A2R8Y6A3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152192
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461852
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152192
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Congenital myopathy with fiber type disproportion Uncertain:1
Feb 22, 2019
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.48
.;T;.
Eigen
Benign
-0.18
Eigen_PC
Benign
0.070
FATHMM_MKL
Benign
0.71
D
LIST_S2
Benign
0.69
.;T;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.21
T;T;T
MetaSVM
Benign
-0.81
T
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
0.59
N;N;.
REVEL
Benign
0.26
Sift
Benign
0.18
T;T;.
Sift4G
Benign
0.18
T;T;.
Polyphen
0.0
B;.;B
Vest4
0.14
MutPred
0.41
Gain of phosphorylation at T259 (P = 0.0405);Gain of phosphorylation at T259 (P = 0.0405);Gain of phosphorylation at T259 (P = 0.0405);
MVP
0.70
MPC
0.92
ClinPred
0.41
T
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1197412497; hg19: chr9-35682157; API