rs2145925

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003289.4(TPM2):c.115-105A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 1,545,900 control chromosomes in the GnomAD database, including 153,369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 15688 hom., cov: 33)

Exomes 𝑓: 0.44 ( 137681 hom. )

Consequence

TPM2
NM_003289.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: -1.84

Publications

9 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 9-35689376-T-C is Benign according to our data. Variant chr9-35689376-T-C is described in ClinVar as Benign. ClinVar VariationId is 140484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM2	NM_003289.4 link	c.115-105A>G		intron_variant	Intron 1 of 8	ENST00000645482.3	NP_003280.2	P07951-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM2	ENST00000645482.3 link	c.115-105A>G		intron_variant	Intron 1 of 8		NM_003289.4	ENSP00000496494.2		P07951-1

Frequencies

GnomAD3 genomes

AF:

0.453

AC:

68785

AN:

151966

Hom.:

15675

Cov.:

show subpopulations

Gnomad AFR

AF:

0.473

Gnomad AMI

AF:

0.576

Gnomad AMR

AF:

0.393

Gnomad ASJ

AF:

0.454

Gnomad EAS

AF:

0.626

Gnomad SAS

AF:

0.491

Gnomad FIN

AF:

0.474

Gnomad MID

AF:

0.453

Gnomad NFE

AF:

0.433

Gnomad OTH

AF:

0.460

GnomAD4 exome

AF:

0.442

AC:

616701

AN:

1393816

Hom.:

137681

Cov.:

AF XY:

0.444

AC XY:

305766

AN XY:

688726

show subpopulations

African (AFR)

AF:

0.472

AC:

14927

AN:

31654

American (AMR)

AF:

0.360

AC:

12835

AN:

35660

Ashkenazi Jewish (ASJ)

AF:

0.455

AC:

10385

AN:

22804

East Asian (EAS)

AF:

0.626

AC:

24185

AN:

38650

South Asian (SAS)

AF:

0.490

AC:

37889

AN:

77360

European-Finnish (FIN)

AF:

0.479

AC:

19907

AN:

41530

Middle Eastern (MID)

AF:

0.406

AC:

1839

AN:

4526

European-Non Finnish (NFE)

AF:

0.433

AC:

469064

AN:

1083838

Other (OTH)

AF:

0.444

AC:

25670

AN:

57794

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

19168

38337

57505

76674

95842

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14608

29216

43824

58432

73040

<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:

0.453

AC:

68826

AN:

152084

Hom.:

15688

Cov.:

AF XY:

0.454

AC XY:

33761

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.472

AC:

19598

AN:

41504

American (AMR)

AF:

0.393

AC:

6013

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.454

AC:

1575

AN:

3472

East Asian (EAS)

AF:

0.626

AC:

3229

AN:

5158

South Asian (SAS)

AF:

0.492

AC:

2373

AN:

4822

European-Finnish (FIN)

AF:

0.474

AC:

5010

AN:

10576

Middle Eastern (MID)

AF:

0.466

AC:

137

AN:

294

European-Non Finnish (NFE)

AF:

0.433

AC:

29390

AN:

67942

Other (OTH)

AF:

0.463

AC:

977

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1988

3976

5964

7952

9940

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

646

1292

1938

2584

3230

<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:

0.439

Hom.:

21232

Bravo

AF:

0.449

Asia WGS

AF:

0.577

AC:

2008

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other: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

- -

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

3.1

(source)

DANN

Benign

0.51

PhyloP100

-1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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