9-35689795-ATCTTCT-ATCT

Variant names:

• chr9-35689795-ATCT-A
• rs199476146
• NM_003289.4:c.20_22delAGA

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_003289.4(TPM2):​c.20_22delAGA​(p.Lys7del) 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000709984: 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" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TPM2 NM_003289.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 7.96
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• TPM2-related myopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arthrogryposis, distal, type 1A

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• congenital myopathy 23

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• congenital myopathy

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• cap myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• digitotalar dysmorphism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Sheldon-hall syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000709984: 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); SCV004013507: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23378224, 23413262, 26307083).; SCV000934833: Experimental studies have shown that this variant affects TPM2 function (PMID: 23378224, 23413262, 26307083).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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 9-35689795-ATCT-A is Pathogenic according to our data. Variant chr9-35689795-ATCT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 140486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003289.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM2	NM_003289.4	MANE Select	c.20_22delAGA	p.Lys7del	disruptive_inframe_deletion	Exon 1 of 9	NP_003280.2
	TPM2	NM_001301226.2		c.20_22delAGA	p.Lys7del	disruptive_inframe_deletion	Exon 1 of 9	NP_001288155.1	Q5TCU3
	TPM2	NM_001301227.2		c.20_22delAGA	p.Lys7del	disruptive_inframe_deletion	Exon 1 of 9	NP_001288156.1	A7XZE4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM2	ENST00000645482.3	MANE Select	c.20_22delAGA	p.Lys7del	disruptive_inframe_deletion	Exon 1 of 9	ENSP00000496494.2	P07951-1
	TPM2	ENST00000378292.9	TSL:1	c.20_22delAGA	p.Lys7del	disruptive_inframe_deletion	Exon 1 of 9	ENSP00000367542.3	P07951-2
	TPM2	ENST00000951580.1		c.20_22delAGA	p.Lys7del	disruptive_inframe_deletion	Exon 1 of 10	ENSP00000621639.1

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Congenital myopathy 23 (3)
2	-	-	not provided (3)
1	-	-	Arthrogryposis, distal, type 1A (1)
1	-	-	Arthrogryposis, distal, type 1A;C1836447:Congenital myopathy 23 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=45/55	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199476146; hg19: chr9-35689792; COSMIC: COSV61406611; COSMIC: COSV61406611;