rs56249943

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_003289.4(TPM2):c.*8G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0855 in 1,552,166 control chromosomes in the GnomAD database, including 6,178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.063 ( 372 hom., cov: 32)

Exomes 𝑓: 0.088 ( 5806 hom. )

Consequence

TPM2
NM_003289.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: -0.423

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

TPM2-related myopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
arthrogryposis, distal, type 1A
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
congenital myopathy 23
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
congenital myopathy
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
cap myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
childhood-onset nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
congenital fiber-type disproportion myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
digitotalar dysmorphism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Sheldon-hall syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
typical nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TPM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 9-35683151-C-T is Benign according to our data. Variant chr9-35683151-C-T is described in CliVar as Benign. Clinvar id is 94122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35683151-C-T is described in CliVar as Benign. Clinvar id is 94122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35683151-C-T is described in CliVar as Benign. Clinvar id is 94122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35683151-C-T is described in CliVar as Benign. Clinvar id is 94122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35683151-C-T is described in CliVar as Benign. Clinvar id is 94122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0915 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TPM2	NM_003289.4 link	c.*8G>A	3_prime_UTR_variant	Exon 9 of 9	ENST00000645482.3	NP_003280.2	P07951-1
TPM2	NM_001301227.2 link	c.*8G>A	3_prime_UTR_variant	Exon 9 of 9		NP_001288156.1	A7XZE4V9HW25
TPM2	NM_001301226.2 link	c.773-988G>A	intron_variant	Intron 8 of 8		NP_001288155.1	Q5TCU3V9HW25
TPM2	NM_213674.1 link	c.773-988G>A	intron_variant	Intron 8 of 8		NP_998839.1	P07951-2V9HW25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM2	ENST00000645482.3 link	c.*8G>A		3_prime_UTR_variant	Exon 9 of 9		NM_003289.4	ENSP00000496494.2		P07951-1

Frequencies

GnomAD3 genomes

AF:

0.0632

AC:

9609

AN:

152014

Hom.:

372

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0148

Gnomad AMI

AF:

0.239

Gnomad AMR

AF:

0.0650

Gnomad ASJ

AF:

0.0859

Gnomad EAS

AF:

0.0284

Gnomad SAS

AF:

0.0759

Gnomad FIN

AF:

0.0418

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.0934

Gnomad OTH

AF:

0.0692

GnomAD2 exomes

AF:

0.0760

AC:

12096

AN:

159072

AF XY:

0.0785

show subpopulations

Gnomad AFR exome

AF:

0.0138

Gnomad AMR exome

AF:

0.0717

Gnomad ASJ exome

AF:

0.0904

Gnomad EAS exome

AF:

0.0327

Gnomad FIN exome

AF:

0.0460

Gnomad NFE exome

AF:

0.0976

Gnomad OTH exome

AF:

0.0762

GnomAD4 exome

AF:

0.0879

AC:

123047

AN:

1400034

Hom.:

5806

Cov.:

AF XY:

0.0885

AC XY:

61092

AN XY:

690674

show subpopulations

African (AFR)

AF:

0.0139

AC:

440

AN:

31602

American (AMR)

AF:

0.0701

AC:

2518

AN:

35896

Ashkenazi Jewish (ASJ)

AF:

0.0883

AC:

2229

AN:

25246

East Asian (EAS)

AF:

0.0215

AC:

769

AN:

35818

South Asian (SAS)

AF:

0.0840

AC:

6669

AN:

79426

European-Finnish (FIN)

AF:

0.0466

AC:

2295

AN:

49282

Middle Eastern (MID)

AF:

0.0723

AC:

412

AN:

5698

European-Non Finnish (NFE)

AF:

0.0953

AC:

102860

AN:

1079032

Other (OTH)

AF:

0.0837

AC:

4855

AN:

58034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

7323

14645

21968

29290

36613

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3716

7432

11148

14864

18580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0632

AC:

9614

AN:

152132

Hom.:

372

Cov.:

AF XY:

0.0608

AC XY:

4525

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0147

AC:

610

AN:

41528

American (AMR)

AF:

0.0650

AC:

994

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0859

AC:

298

AN:

3468

East Asian (EAS)

AF:

0.0285

AC:

147

AN:

5160

South Asian (SAS)

AF:

0.0757

AC:

365

AN:

4820

European-Finnish (FIN)

AF:

0.0418

AC:

443

AN:

10590

Middle Eastern (MID)

AF:

0.133

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0935

AC:

6351

AN:

67956

Other (OTH)

AF:

0.0704

AC:

149

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

405

810

1215

1620

2025

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

118

236

354

472

590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0851

Hom.:

281

Bravo

AF:

0.0653

Asia WGS

AF:

0.0620

AC:

216

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Jan 16, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

*8G>A in exon 9A of TPM2: This variant is not expected to have clinical signific ance because it has been identified in 8.9% (757/8480) of European American chro mosomes from a broad population by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu/EVS; dbSNP rs56249943). -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

TPM2 homepage - Leiden Muscular Dystrophy pages

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Arthrogryposis, distal, type 1A

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Congenital myopathy 23

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.65

(source)

DANN

Benign

0.85

PhyloP100

-0.42

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over