rs199476147

Positions:

• chr9-35689238-GCTT-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP5_Moderate

The NM_003289.4(TPM2):​c.145_147delAAG​(p.Lys49del) variant causes a conservative inframe deletion change. 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 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 6.26

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a region_of_interest Disordered (size 64) in uniprot entity TPM2_HUMAN there are 5 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 9-35689238-GCTT-G is Pathogenic according to our data. Variant chr9-35689238-GCTT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12466.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-35689238-GCTT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM2	NM_003289.4	c.145_147delAAG	p.Lys49del	conservative_inframe_deletion	2/9	ENST00000645482.3	NP_003280.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM2	ENST00000645482.3	c.145_147delAAG	p.Lys49del	conservative_inframe_deletion	2/9		NM_003289.4	ENSP00000496494.2

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arthrogryposis, distal, type 1A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 10, 2023

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 have shown that this variant affects TPM2 function (PMID: 22084935, 23886664, 24039757). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This variant has been observed in individual(s) with clinical features of autosomal dominant congenital myopathy (PMID: 19047562). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This variant, c.145_147del, results in the deletion of 1 amino acid(s) of the TPM2 protein (p.Lys49del), but otherwise preserves the integrity of the reading frame. -

Congenital myopathy 23 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 02, 2008

- -

not provided Other:1

not provided, no classification provided

literature only

TPM2 homepage - Leiden Muscular Dystrophy pages

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Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs199476147; hg19: chr9-35689235;