rs137853307

chr9-35684765-G-Cchr9-35684765-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1 PM1 PM2 PP2 PP3_Moderate PP5

The NM_003289.4(TPM2):c.606C>G(p.Asn202Lys) 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 (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM2 NM_003289.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 10.0

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.

• PS1: Transcript NM_003289.4 (TPM2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 939822
• PM1: In a coiled_coil_region (size 283) in uniprot entity TPM2_HUMAN there are 62 pathogenic changes around while only 5 benign (93%) in NM_003289.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TPM2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919
• PP5: Variant 9-35684765-G-C is Pathogenic according to our data. Variant chr9-35684765-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 12467.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-35684765-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM2	NM_003289.4	c.606C>G	p.Asn202Lys	missense_variant	6/9	ENST00000645482.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM2	ENST00000645482.3	c.606C>G	p.Asn202Lys	missense_variant	6/9		NM_003289.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital myopathy 23 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 02, 2008

- -

not provided Other:1

not provided, no classification provided

literature only

TPM2 homepage - Leiden Muscular Dystrophy pages

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;D;D;D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T;.;T;T
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationTaster	Benign	1.0	A;A;A;A
PROVEAN	Uncertain	-3.3	D;.;D;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0020	D;.;D;.
Sift4G	Benign	0.13	T;.;T;D
Polyphen		0.0030	.;B;B;.
Vest4		0.93
MutPred		0.79		Gain of ubiquitination at N202 (P = 0.0146);Gain of ubiquitination at N202 (P = 0.0146);Gain of ubiquitination at N202 (P = 0.0146);.;
MVP		0.95
ClinPred		0.97	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs137853307; hg19: chr9-35684762;