9-35683177-A-AT

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_003289.4(TPM2):c.836_837insA(p.Asn279LysfsTer2) variant causes a frameshift 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: 33)
• Consequence: TPM2 NM_003289.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.01

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0222 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-35683177-A-AT is Pathogenic according to our data. Variant chr9-35683177-A-AT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2634361.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM2	NM_003289.4	c.836_837insA	p.Asn279LysfsTer2	frameshift_variant	9/9	ENST00000645482.3
TPM2	NM_001301227.2	c.836_837insA	p.Asn279LysfsTer2	frameshift_variant	9/9
TPM2	NM_001301226.2	c.773-1015_773-1014insA		intron_variant
TPM2	NM_213674.1	c.773-1015_773-1014insA		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM2	ENST00000645482.3	c.836_837insA	p.Asn279LysfsTer2	frameshift_variant	9/9		NM_003289.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

TPM2-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 31, 2023

The TPM2 c.836dupA variant is predicted to result in a frameshift and premature protein termination (p.Asn279Lysfs*2). This variant occurs in the last exon of the TPM2 gene and likely does not result in nonsense-mediated decay and only shortens the protein by five amino acids. To our knowledge, this variant has not been reported in the literature or public databases, indicating it is rare (http://gnomad.broadinstitute.org). At PreventionGenetics, we have observed the c.836dupA in an additional patient with features consistent with a TPM2-related disorder (internal data). We interpret this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-35683174;