dbSNP rs1554658995: TPM2:p.Asp121del (chr9-35685655-CTCA-C) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM4_SupportingPP5_Moderate

The NM_003289.4(TPM2):c.363_365delTGA(p.Asp121del) variant causes a disruptive inframe deletion 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: 32)

Consequence

TPM2
NM_003289.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.90

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a region_of_interest Disordered (size 19) in uniprot entity TPM2_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_003289.4

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_003289.4. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 9-35685655-CTCA-C is Pathogenic according to our data. Variant chr9-35685655-CTCA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 458722.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM2	NM_003289.4 link	c.363_365delTGA	p.Asp121del	disruptive_inframe_deletion	Exon 3 of 9	ENST00000645482.3	NP_003280.2	P07951-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM2	ENST00000645482.3 link	c.363_365delTGA	p.Asp121del	disruptive_inframe_deletion	Exon 3 of 9		NM_003289.4	ENSP00000496494.2		P07951-1

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Arthrogryposis, distal, type 1A

Pathogenic:1

May 09, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This variant, c.363_365delTGA, results in the deletion of 1 amino acids of the TPM2 protein (p.Asp121del), but otherwise preserves the integrity of the reading frame. This variant has not been reported in the literature in individuals with TPM2-related disease. However, family studies have indicated that this variant was not present in the parents of an individual affected with nemaline myopathy, which suggests that it was de novo in that affected individual (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing