9-35684825-CG-CGGG

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_003289.4(TPM2):c.564-20_564-19dupCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,594,158 control chromosomes in the GnomAD database, including 14 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 4 hom., cov: 0)

Exomes 𝑓: 0.0019 ( 10 hom. )

Consequence

TPM2
NM_003289.4 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.39

Publications

6 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), PanelApp Australia, G2P
congenital myopathy 23
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, 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 9-35684825-C-CGG is Benign according to our data. Variant chr9-35684825-C-CGG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1565934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00193 (291/150634) while in subpopulation EAS AF = 0.012 (61/5084). AF 95% confidence interval is 0.00959. There are 4 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

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	UniProt
TPM2	NM_003289.4	MANE Select	c.564-20_564-19dupCC	intron	N/A	NP_003280.2
TPM2	NM_001301226.2		c.564-20_564-19dupCC	intron	N/A	NP_001288155.1	Q5TCU3
TPM2	NM_001301227.2		c.639+237_639+238dupCC	intron	N/A	NP_001288156.1	A7XZE4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TPM2	ENST00000645482.3	MANE Select	c.564-20_564-19dupCC	intron	N/A	ENSP00000496494.2	P07951-1
TPM2	ENST00000378292.9	TSL:1	c.639+237_639+238dupCC	intron	N/A	ENSP00000367542.3	P07951-2
TPM2	ENST00000951580.1		c.640-81_640-80dupCC	intron	N/A	ENSP00000621639.1

Frequencies

GnomAD3 genomes

AF:

0.00191

AC:

288

AN:

150518

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000663

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00172

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.0120

Gnomad SAS

AF:

0.00105

Gnomad FIN

AF:

0.00698

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00123

Gnomad OTH

AF:

0.00485

GnomAD4 exome

AF:

0.00191

AC:

2754

AN:

1443524

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

1371

AN XY:

717934

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000697

AC:

AN:

32996

American (AMR)

AF:

0.00209

AC:

AN:

43534

Ashkenazi Jewish (ASJ)

AF:

0.00117

AC:

AN:

25712

East Asian (EAS)

AF:

0.0143

AC:

563

AN:

39304

South Asian (SAS)

AF:

0.00233

AC:

198

AN:

85128

European-Finnish (FIN)

AF:

0.00779

AC:

408

AN:

52392

Middle Eastern (MID)

AF:

0.00140

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00115

AC:

1264

AN:

1099116

Other (OTH)

AF:

0.00283

AC:

169

AN:

59644

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

138

276

414

552

690

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.00193

AC:

291

AN:

150634

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

148

AN XY:

73496

show subpopulations

African (AFR)

AF:

0.000661

AC:

AN:

40876

American (AMR)

AF:

0.00172

AC:

AN:

15156

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.0120

AC:

AN:

5084

South Asian (SAS)

AF:

0.00105

AC:

AN:

4762

European-Finnish (FIN)

AF:

0.00698

AC:

AN:

10308

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00123

AC:

AN:

67698

Other (OTH)

AF:

0.00625

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00178

Hom.:

2743

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Arthrogryposis, distal, type 1A (1)

Arthrogryposis, distal, type 1A;C0546264:Congenital myopathy with fiber type disproportion;C1836447:Congenital myopathy 23 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.4

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Computational scores

Splicing

Publications

Other links and lift over