rs199476146

chr9-35689795-ATCT-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM4_Supporting PP3 PP5_Very_Strong

The NM_003289.4(TPM2):c.20_22del(p.Lys7del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TPM2 NM_003289.4 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.96

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a region_of_interest Disordered (size 64) in uniprot entity TPM2_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_003289.4
• PM4: Nonframeshift variant in NON repetitive region in NM_003289.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 9-35689795-ATCT-A is Pathogenic according to our data. Variant chr9-35689795-ATCT-A is described in ClinVar as [Pathogenic]. Clinvar id is 140486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35689795-ATCT-A is described in Lovd as [Pathogenic]. Variant chr9-35689795-ATCT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM2	NM_003289.4	c.20_22del	p.Lys7del	inframe_deletion	1/9	ENST00000645482.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM2	ENST00000645482.3	c.20_22del	p.Lys7del	inframe_deletion	1/9		NM_003289.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myopathy 23 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is not observed in the gnomAD v2.1.1 dataset. Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23378224, 23413262, 26307083). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 22980765, 23378224, 23413262). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000140486). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Sep 23, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2023	- -

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2023	Published functional studies support that c.20_22delAGA results in a protein with impaired localization, altered sarcomere structure, and impaired function (Mokbel et al., 2013; Davidson et al., 2013); In-frame deletion of 1 amino acids in a non-repeat region; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26307083, 31060721, 23378224, 23413262, 22980765, 27726070, 25214167, 33060286, 35579956, 36233295) -
not provided, no classification provided	literature only	TPM2 homepage - Leiden Muscular Dystrophy pages	-	- -

Arthrogryposis, distal, type 1A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 05, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects TPM2 function (PMID: 23378224, 23413262, 26307083). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 140486). This variant is also known as c.19_21delAAG. This variant has been observed in individual(s) with autosomal dominant congenital myopathy (PMID: 22980765, 23378224, 23413262). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant, c.20_22del, results in the deletion of 1 amino acid(s) of the TPM2 protein (p.Lys7del), but otherwise preserves the integrity of the reading frame. -

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: rs199476146; hg19: chr9-35689792;