rs137853306

Variant names:

• chr9-35689265-C-T
• rs137853306
• NM_003289.4:c.121G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_003289.4(TPM2):​c.121G>A​(p.Glu41Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV001377621: Experimental studies have shown that this missense change affects TPM2 function (PMID:18420702, 22084935, 24039757, 25978979).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM2 NM_003289.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.89
• Publications: 14 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 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001377621: Experimental studies have shown that this missense change affects TPM2 function (PMID: 18420702, 22084935, 24039757, 25978979).
• 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: 3.2995 (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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881
• PP5: Variant 9-35689265-C-T is Pathogenic according to our data. Variant chr9-35689265-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 12464.Status of the report is criteria_provided_single_submitter, 1 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.121G>A	p.Glu41Lys	missense	Exon 2 of 9	NP_003280.2
	TPM2	NM_001301226.2		c.121G>A	p.Glu41Lys	missense	Exon 2 of 9	NP_001288155.1	Q5TCU3
	TPM2	NM_001301227.2		c.121G>A	p.Glu41Lys	missense	Exon 2 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.121G>A	p.Glu41Lys	missense	Exon 2 of 9	ENSP00000496494.2	P07951-1
	TPM2	ENST00000378292.9	TSL:1	c.121G>A	p.Glu41Lys	missense	Exon 2 of 9	ENSP00000367542.3	P07951-2
	TPM2	ENST00000951580.1		c.121G>A	p.Glu41Lys	missense	Exon 2 of 10	ENSP00000621639.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Arthrogryposis, distal, type 1A (1)
1	-	-	Congenital myopathy 23 (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.16	T
Polyphen		0.46	P
Vest4		0.50
MutPred		0.72		Gain of MoRF binding (P = 0.0025)
MVP		0.90
MPC		1.3
ClinPred		0.95	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.29
gMVP		0.97
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs137853306; hg19: chr9-35689262;