ENST00000378292.9:c.829A>C

Variant names:

• chr9-35682107-T-G
• rs568393322
• ENST00000378292.9:c.829A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The ENST00000378292.9(TPM2):​c.829A>C​(p.Thr277Pro) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T277A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM2 ENST00000378292.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.69

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 7 ACMG points.

• PM1: In a coiled_coil_region (size 283) in uniprot entity TPM2_HUMAN there are 57 pathogenic changes around while only 3 benign (95%) in ENST00000378292.9
• 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: 3.2245 (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, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM2	NM_001301226.2	c.829A>C	p.Thr277Pro	missense_variant	Exon 9 of 9		NP_001288155.1
TPM2	NM_213674.1	c.829A>C	p.Thr277Pro	missense_variant	Exon 9 of 9		NP_998839.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM2	ENST00000378292.9	c.829A>C	p.Thr277Pro	missense_variant	Exon 9 of 9	1		ENSP00000367542.3
TPM2	ENST00000329305.6	c.829A>C	p.Thr277Pro	missense_variant	Exon 9 of 9	2		ENSP00000367541.1
TPM2	ENST00000644325	c.*601A>C		3_prime_UTR_variant	Exon 4 of 4			ENSP00000495075.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;D;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	.;T;T
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.0	D;D;N
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D;T
Sift4G	Uncertain	0.0040	D;D;.
Polyphen		0.69	P;.;P
Vest4		0.67
MutPred		0.73		Loss of stability (P = 0.0979);Loss of stability (P = 0.0979);Loss of stability (P = 0.0979);
MVP		0.94
MPC		2.4
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7

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: rs568393322; hg19: chr9-35682104;