chr9-35682120-C-A

Variant names:

• chr9-35682120-C-A
• ENST00000378292.9:c.816G>T
• TPM2 p.Gln272His

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_213674.1(TPM2):​c.816G>T​(p.Gln272His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM2 NM_213674.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.21
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the TPM2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 19 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.1346 (below the threshold of 3.09). Trascript score misZ: 3.2245 (above the threshold of 3.09). GenCC associations: The gene is linked to congenital myopathy 23, arthrogryposis, distal, type 1A, congenital myopathy, digitotalar dysmorphism, TPM2-related myopathy, congenital fiber-type disproportion myopathy, cap myopathy, childhood-onset nemaline myopathy, Sheldon-hall syndrome, typical nemaline myopathy.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213674.1. 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_001301226.2		c.816G>T	p.Gln272His	missense	Exon 9 of 9	NP_001288155.1	Q5TCU3
	TPM2	NM_213674.1		c.816G>T	p.Gln272His	missense	Exon 9 of 9	NP_998839.1	P07951-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM2	ENST00000378292.9	TSL:1	c.816G>T	p.Gln272His	missense	Exon 9 of 9	ENSP00000367542.3	P07951-2
	TPM2	ENST00000329305.6	TSL:2	c.816G>T	p.Gln272His	missense	Exon 9 of 9	ENSP00000367541.1	Q5TCU3
	TPM2	ENST00000951578.1		c.*1039G>T		3_prime_UTR	Exon 9 of 9	ENSP00000621637.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.081	D
PhyloP100		2.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.50
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.0070	D
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Mutation Taster		=65/35	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr9-35682117;