9-35684765-G-T

Variant names:

• chr9-35684765-G-T
• rs137853307
• NM_003289.4:c.606C>A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1 PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_003289.4(TPM2):​c.606C>A​(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 Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM2 NM_003289.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P: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 13 ACMG points.

• PS1: Transcript NM_003289.4 (TPM2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a coiled_coil_region (size 283) in uniprot entity TPM2_HUMAN there are 37 pathogenic changes around while only 3 benign (93%) in NM_003289.4
• 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 cap myopathy, typical nemaline myopathy, digitotalar dysmorphism, congenital fiber-type disproportion myopathy, childhood-onset nemaline myopathy, congenital myopathy 23, Sheldon-hall syndrome, arthrogryposis, distal, type 1A, TPM2-related myopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 9-35684765-G-T is Pathogenic according to our data. Variant chr9-35684765-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 939822.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM2	NM_003289.4	c.606C>A	p.Asn202Lys	missense_variant	Exon 6 of 9	ENST00000645482.3	NP_003280.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM2	ENST00000645482.3	c.606C>A	p.Asn202Lys	missense_variant	Exon 6 of 9		NM_003289.4	ENSP00000496494.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arthrogryposis, distal, type 1A Pathogenic:1

Nov 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 939822). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 202 of the TPM2 protein (p.Asn202Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of TPM2-related conditions (PMID: 19047562, 22980765; Invitae). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TPM2 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

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	27
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	0.57	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	4.2	.;H;H;.
PROVEAN	Uncertain	-3.3	D;.;D;.
REVEL	Pathogenic	0.74
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
Varity_R		0.50
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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;