9-35683243-TGGGGGG-TGGGGGGG

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_003289.4(TPM2):c.773-3dupC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 1,484,044 control chromosomes in the GnomAD database, including 61,278 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 6387 hom., cov: 0)

Exomes 𝑓: 0.32 ( 54891 hom. )

Consequence

TPM2
NM_003289.4 splice_region, intron

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 1.23

Publications

10 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 -16 ACMG points.

BP6

Variant 9-35683243-T-TG is Benign according to our data. Variant chr9-35683243-T-TG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003289.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TPM2	NM_003289.4	MANE Select	c.773-3dupC	splice_region intron	N/A	NP_003280.2
TPM2	NM_001301226.2		c.772+1002dupC	intron	N/A	NP_001288155.1
TPM2	NM_001301227.2		c.773-3dupC	splice_region intron	N/A	NP_001288156.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TPM2	ENST00000645482.3	MANE Select	c.773-3_773-2insC	splice_region intron	N/A	ENSP00000496494.2
TPM2	ENST00000378292.9	TSL:1	c.772+1002_772+1003insC	intron	N/A	ENSP00000367542.3
TPM2	ENST00000329305.6	TSL:2	c.772+1002_772+1003insC	intron	N/A	ENSP00000367541.1

Frequencies

GnomAD3 genomes

AF:

0.267

AC:

40146

AN:

150290

Hom.:

6392

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0844

Gnomad AMI

AF:

0.421

Gnomad AMR

AF:

0.326

Gnomad ASJ

AF:

0.356

Gnomad EAS

AF:

0.264

Gnomad SAS

AF:

0.276

Gnomad FIN

AF:

0.247

Gnomad MID

AF:

0.377

Gnomad NFE

AF:

0.359

Gnomad OTH

AF:

0.270

GnomAD2 exomes

AF:

0.300

AC:

46173

AN:

154034

AF XY:

0.301

show subpopulations

Gnomad AFR exome

AF:

0.101

Gnomad AMR exome

AF:

0.330

Gnomad ASJ exome

AF:

0.338

Gnomad EAS exome

AF:

0.248

Gnomad FIN exome

AF:

0.244

Gnomad NFE exome

AF:

0.346

Gnomad OTH exome

AF:

0.318

GnomAD4 exome

AF:

0.320

AC:

426562

AN:

1333638

Hom.:

54891

Cov.:

AF XY:

0.319

AC XY:

210613

AN XY:

659816

show subpopulations

African (AFR)

AF:

0.0933

AC:

2828

AN:

30314

American (AMR)

AF:

0.318

AC:

11263

AN:

35390

Ashkenazi Jewish (ASJ)

AF:

0.324

AC:

7879

AN:

24350

East Asian (EAS)

AF:

0.217

AC:

7652

AN:

35196

South Asian (SAS)

AF:

0.267

AC:

20903

AN:

78170

European-Finnish (FIN)

AF:

0.245

AC:

11755

AN:

48018

Middle Eastern (MID)

AF:

0.289

AC:

1595

AN:

5522

European-Non Finnish (NFE)

AF:

0.338

AC:

345552

AN:

1021196

Other (OTH)

AF:

0.309

AC:

17135

AN:

55482

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

14194

28389

42583

56778

70972

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11546

23092

34638

46184

57730

<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:

0.267

AC:

40138

AN:

150406

Hom.:

6387

Cov.:

AF XY:

0.264

AC XY:

19388

AN XY:

73458

show subpopulations

African (AFR)

AF:

0.0845

AC:

3432

AN:

40630

American (AMR)

AF:

0.326

AC:

4940

AN:

15176

Ashkenazi Jewish (ASJ)

AF:

0.356

AC:

1231

AN:

3462

East Asian (EAS)

AF:

0.264

AC:

1346

AN:

5100

South Asian (SAS)

AF:

0.274

AC:

1302

AN:

4746

European-Finnish (FIN)

AF:

0.247

AC:

2555

AN:

10364

Middle Eastern (MID)

AF:

0.378

AC:

111

AN:

294

European-Non Finnish (NFE)

AF:

0.359

AC:

24278

AN:

67640

Other (OTH)

AF:

0.269

AC:

561

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

1236

2472

3707

4943

6179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

412

824

1236

1648

2060

<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:

0.237

Hom.:

621

Bravo

AF:

0.269

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Jan 16, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:no assertion criteria provided

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

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:2Other:1

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

TPM2 homepage - Leiden Muscular Dystrophy pages

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Jun 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arthrogryposis, distal, type 1A

Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nemaline Myopathy, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arthrogryposis multiplex congenita

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.2

Mutation Taster

=96/4

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over