9-35683230-C-A

Position:

• chr9-35683230-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_003289.4(TPM2):​c.784G>T​(p.Ala262Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TPM2 NM_003289.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a coiled_coil_region (size 283) in uniprot entity TPM2_HUMAN there are 64 pathogenic changes around while only 4 benign (94%) 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2508833).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM2	NM_003289.4	c.784G>T	p.Ala262Ser	missense_variant	9/9	ENST00000645482.3
TPM2	NM_001301227.2	c.784G>T	p.Ala262Ser	missense_variant	9/9
TPM2	NM_001301226.2	c.772+1016G>T		intron_variant
TPM2	NM_213674.1	c.772+1016G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM2	ENST00000645482.3	c.784G>T	p.Ala262Ser	missense_variant	9/9		NM_003289.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1388884 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 685742

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myopathy 23 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant c.784G>T (p.Ala262Ser) in TPM2 (NM_001301227.1) gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ala262Ser variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Ala at position 262 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Ala262Ser in TPM2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.49	T;T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.018
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	.;D;D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	0.47	N;N;.
MutationTaster	Benign	0.93	D;D;D;D
PROVEAN	Benign	-0.11	.;N;.
REVEL	Uncertain	0.35
Sift	Benign	0.54	.;T;.
Sift4G	Benign	0.55	.;T;.
Polyphen		0.0	B;B;B
Vest4		0.17
MutPred		0.57		Gain of disorder (P = 0.0444);Gain of disorder (P = 0.0444);Gain of disorder (P = 0.0444);
MVP		0.96
ClinPred		0.40	T
GERP RS		5.0
Varity_R		0.089
gMVP		0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-35683227;