rs104894129

chr9-35685672-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_003289.4(TPM2):c.349G>A(p.Glu117Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E117A) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TPM2 NM_003289.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:2
• Conservation: PhyloP100: 6.17

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 19 ACMG points.

• PM1: In a region_of_interest Disordered (size 19) in uniprot entity TPM2_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_003289.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP2: Missense variant where missense usually causes diseases, TPM2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 9-35685672-C-T is Pathogenic according to our data. Variant chr9-35685672-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35685672-C-T is described in Lovd as [Pathogenic]. Variant chr9-35685672-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM2	NM_003289.4	c.349G>A	p.Glu117Lys	missense_variant	3/9	ENST00000645482.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM2	ENST00000645482.3	c.349G>A	p.Glu117Lys	missense_variant	3/9		NM_003289.4	A1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74432

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

not provided, no classification provided	literature only	TPM2 homepage - Leiden Muscular Dystrophy pages	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2021	Published functional studies demonstrate a damaging effect showing the variant to significantly inhibit formation of strong binding actomyosin disruptive to the ATPase cycle, impaired activation of contractility, and reduction in thin filament activation (Marttila et al., 2012; Karpicheva et al., 2013; Karpicheva et al., 2014); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24692096, 22084935, 11738357, 31321302, 24077912, 27535533, 23689010, 24657080) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2017	- -

Congenital myopathy 23 Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2002	- -

Arthrogryposis, distal, type 1A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 18, 2022

ClinVar contains an entry for this variant (Variation ID: 12462). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPM2 function (PMID: 22084935, 23689010, 23886664, 24657080). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with congenital fiber type disproportion (CFTD), distal arthrogryposis (DA) and nemaline myopathy (NM) (PMID: 11738357, 24692096). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 117 of the TPM2 protein (p.Glu117Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	4.2	H;.;H;H;H;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.9	D;D;D;.;D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;.;D;.
Sift4G	Uncertain	0.043	D;T;T;.;T;.
Polyphen		1.0	D;.;D;P;P;D
Vest4		0.90
MutPred		0.82		Gain of MoRF binding (P = 0.007);Gain of MoRF binding (P = 0.007);Gain of MoRF binding (P = 0.007);Gain of MoRF binding (P = 0.007);Gain of MoRF binding (P = 0.007);Gain of MoRF binding (P = 0.007);
MVP		0.97
MPC		2.3
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.61
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894129; hg19: chr9-35685669;