chr9-35689265-C-T

Position:

• chr9-35689265-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 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 (★).

• 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

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 9 ACMG points.

• PM1: In a region_of_interest Disordered (size 64) in uniprot entity TPM2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_003289.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TPM2. . Gene score misZ 2.1346 (greater than the threshold 3.09). Trascript score misZ 3.2995 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.881
• PP5: Variant 9-35689265-C-T is Pathogenic according to our data. Variant chr9-35689265-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12464.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-35689265-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM2	NM_003289.4	c.121G>A	p.Glu41Lys	missense_variant	2/9	ENST00000645482.3	NP_003280.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM2	ENST00000645482.3	c.121G>A	p.Glu41Lys	missense_variant	2/9		NM_003289.4	ENSP00000496494	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arthrogryposis, distal, type 1A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 41 of the TPM2 protein (p.Glu41Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant TPM2-related conditions (PMID: 17846275, 24692096). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12464). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects TPM2 function (PMID: 18420702, 22084935, 24039757, 25978979). For these reasons, this variant has been classified as Pathogenic. -

Congenital myopathy 23 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2007

- -

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	0.66
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	.;T;.;D;D;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	.;D;D;.;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	2.9	M;.;M;M;M;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.1	N;N;N;.;N;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0020	D;D;D;.;D;.
Sift4G	Benign	0.16	T;T;T;.;T;.
Polyphen		0.46	P;.;P;P;P;P
Vest4		0.50
MutPred		0.72		Gain of MoRF binding (P = 0.0025);Gain of MoRF binding (P = 0.0025);Gain of MoRF binding (P = 0.0025);Gain of MoRF binding (P = 0.0025);Gain of MoRF binding (P = 0.0025);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs137853306; hg19: chr9-35689262;