Genetic Variant TPM2:c.773-3dupC (chr9-35683243-T-TG) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -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:10O:1

Conservation

PhyloP100: 1.23

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 Benign. Variant got -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 [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TPM2	NM_003289.4 link	c.773-3dupC	splice_region_variant, intron_variant	Intron 8 of 8	ENST00000645482.3	NP_003280.2	P07951-1
TPM2	NM_001301226.2 link	c.772+1002dupC	intron_variant	Intron 8 of 8		NP_001288155.1	Q5TCU3V9HW25
TPM2	NM_001301227.2 link	c.773-3dupC	splice_region_variant, intron_variant	Intron 8 of 8		NP_001288156.1	A7XZE4V9HW25
TPM2	NM_213674.1 link	c.772+1002dupC	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.773-3_773-2insC		splice_region_variant, intron_variant	Intron 8 of 8		NM_003289.4	ENSP00000496494.2		P07951-1

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

GnomAD3 exomes

AF:

0.300

AC:

46173

AN:

154034

Hom.:

5997

AF XY:

0.301

AC XY:

24387

AN XY:

81146

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 SAS exome

AF:

0.266

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

Gnomad4 AFR exome

AF:

0.0933

Gnomad4 AMR exome

AF:

0.318

Gnomad4 ASJ exome

AF:

0.324

Gnomad4 EAS exome

AF:

0.217

Gnomad4 SAS exome

AF:

0.267

Gnomad4 FIN exome

AF:

0.245

Gnomad4 NFE exome

AF:

0.338

Gnomad4 OTH exome

AF:

0.309

GnomAD4 genome

AF:

0.267

AC:

40138

AN:

150406

Hom.:

6387

Cov.:

AF XY:

0.264

AC XY:

19388

AN XY:

73458

show subpopulations

Gnomad4 AFR

AF:

0.0845

Gnomad4 AMR

AF:

0.326

Gnomad4 ASJ

AF:

0.356

Gnomad4 EAS

AF:

0.264

Gnomad4 SAS

AF:

0.274

Gnomad4 FIN

AF:

0.247

Gnomad4 NFE

AF:

0.359

Gnomad4 OTH

AF:

0.269

Bravo

AF:

0.269

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 16, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: no assertion criteria provided

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

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2Other:1

Jun 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Arthrogryposis, distal, type 1A

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

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 v4.3

Name

Calibrated prediction

Score

Prediction

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.

9-35683243-TGGGGGG-TGGGGGGG

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