9-35683243-TGGGGGG-TGGGGG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_003289.4(TPM2):c.773-3delC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000957 in 1,493,662 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00010 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000095 ( 0 hom. )

Consequence

TPM2
NM_003289.4 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

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: Likely_benign. The variant received -1 ACMG points.

BP6

Variant 9-35683243-TG-T is Benign according to our data. Variant chr9-35683243-TG-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167742.

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.773-3delC	splice_region intron	N/A	NP_003280.2
TPM2	NM_001301226.2		c.772+1002delC	intron	N/A	NP_001288155.1
TPM2	NM_001301227.2		c.773-3delC	splice_region intron	N/A	NP_001288156.1

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

AF:

0.0000997

AC:

AN:

150450

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000493

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000198

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000630

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000886

Gnomad OTH

AF:

0.000484

GnomAD2 exomes

AF:

0.000195

AC:

AN:

154034

AF XY:

0.000197

show subpopulations

Gnomad AFR exome

AF:

0.000120

Gnomad AMR exome

AF:

0.000243

Gnomad ASJ exome

AF:

0.000119

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000118

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000953

AC:

128

AN:

1343094

Hom.:

Cov.:

AF XY:

0.0000963

AC XY:

AN XY:

664250

show subpopulations

African (AFR)

AF:

0.0000975

AC:

AN:

30770

American (AMR)

AF:

0.000254

AC:

AN:

35498

Ashkenazi Jewish (ASJ)

AF:

0.0000409

AC:

AN:

24474

East Asian (EAS)

AF:

0.00

AC:

AN:

35364

South Asian (SAS)

AF:

0.000690

AC:

AN:

78308

European-Finnish (FIN)

AF:

0.0000206

AC:

AN:

48484

Middle Eastern (MID)

AF:

0.000540

AC:

AN:

5554

European-Non Finnish (NFE)

AF:

0.0000447

AC:

AN:

1028746

Other (OTH)

AF:

0.000197

AC:

AN:

55896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000996

AC:

AN:

150568

Hom.:

Cov.:

AF XY:

0.0000951

AC XY:

AN XY:

73572

show subpopulations

African (AFR)

AF:

0.0000492

AC:

AN:

40660

American (AMR)

AF:

0.000197

AC:

AN:

15194

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5106

South Asian (SAS)

AF:

0.000630

AC:

AN:

4762

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000886

AC:

AN:

67686

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000165

Hom.:

621

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jan 22, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 04, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arthrogryposis, distal, type 1A

Benign:1

Nov 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: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

=54/46

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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