9-35682120-C-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP2BS2

The NM_213674.1(TPM2):c.816G>C(p.Gln272His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

TPM2
NM_213674.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.21

Variant links:

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]

TPM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a coiled_coil_region (size 283) in uniprot entity TPM2_HUMAN there are 34 pathogenic changes around while only 2 benign (94%) in NM_213674.1

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.

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM2	NM_001301226.2 link	c.816G>C	p.Gln272His	missense_variant	Exon 9 of 9		NP_001288155.1	Q5TCU3V9HW25
TPM2	NM_213674.1 link	c.816G>C	p.Gln272His	missense_variant	Exon 9 of 9		NP_998839.1	P07951-2V9HW25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
TPM2	ENST00000378292.9 link	c.816G>C	p.Gln272His	missense_variant	Exon 9 of 9	1	ENSP00000367542.3	P07951-2
TPM2	ENST00000329305.6 link	c.816G>C	p.Gln272His	missense_variant	Exon 9 of 9	2	ENSP00000367541.1	Q5TCU3
TPM2	ENST00000644325 link	c.*588G>C		3_prime_UTR_variant	Exon 4 of 4		ENSP00000495075.1	A0A2R8Y6A3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

250948

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135708

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727234

show subpopulations

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:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jul 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.816G>C (p.Q272H) alteration is located in exon 9 (coding exon 9) of the TPM2 gene. This alteration results from a G to C substitution at nucleotide position 816, causing the glutamine (Q) at amino acid position 272 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

.;D;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.97

.;D;D

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.53

D;D;D

MetaSVM

Uncertain

0.081

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.9

N;N;.

REVEL

Uncertain

0.50

Sift

Uncertain

0.022

D;D;.

Sift4G

Uncertain

0.0070

D;D;.

Polyphen

0.20

B;.;B

Vest4

0.66

MutPred

0.44

Gain of catalytic residue at L274 (P = 0.0562);Gain of catalytic residue at L274 (P = 0.0562);Gain of catalytic residue at L274 (P = 0.0562);

MVP

0.85

MPC

1.6

ClinPred

0.78

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over