9-35682160-G-C

Position:

chr9-35682160-G-C

Variant summary

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

The ENST00000378292.9(TPM2):c.776C>G(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 (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TPM2
ENST00000378292.9 missense

Scores

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]

TPM2 links:

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 56 pathogenic changes around while only 3 benign (95%) in ENST00000378292.9

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 3.2245 (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.

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/exons	MANE	UniProt
TPM2	NM_001301226.2 linkuse as main transcript	c.776C>G	p.Thr259Ser	missense_variant	9/9
TPM2	NM_213674.1 linkuse as main transcript	c.776C>G	p.Thr259Ser	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Appris	UniProt
TPM2	ENST00000378292.9 linkuse as main transcript	c.776C>G	p.Thr259Ser	missense_variant	9/9	1		P07951-2
TPM2	ENST00000329305.6 linkuse as main transcript	c.776C>G	p.Thr259Ser	missense_variant	9/9	2	A1
TPM2	ENST00000644325.1 linkuse as main transcript	c.*548C>G		3_prime_UTR_variant	4/4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

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:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

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:

AN:

152192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Feb 22, 2019

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

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.48

.;T;.

Eigen

Benign

-0.18

Eigen_PC

Benign

0.070

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.69

.;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Benign

-0.81

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Uncertain

0.67

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over