9-35683244-G-GT

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.773-4_773-3insA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,450,610 control chromosomes in the GnomAD database, including 50 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 0.020 ( 23 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 27 hom. )

Consequence

TPM2
NM_003289.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.24

Publications

0 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 9-35683244-G-GT is Benign according to our data. Variant chr9-35683244-G-GT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 366769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0196 (1292/65916) while in subpopulation AFR AF = 0.0524 (1200/22910). AF 95% confidence interval is 0.0499. There are 23 homozygotes in GnomAd4. There are 621 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 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.773-4_773-3insA	splice_region intron	N/A	NP_003280.2
TPM2	NM_001301226.2		c.772+1001_772+1002insA	intron	N/A	NP_001288155.1	Q5TCU3
TPM2	NM_001301227.2		c.773-4_773-3insA	splice_region intron	N/A	NP_001288156.1	A7XZE4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TPM2	ENST00000645482.3	MANE Select	c.773-4_773-3insA	splice_region intron	N/A	ENSP00000496494.2	P07951-1
TPM2	ENST00000378292.9	TSL:1	c.772+1001_772+1002insA	intron	N/A	ENSP00000367542.3	P07951-2
TPM2	ENST00000951580.1		c.788-4_788-3insA	splice_region intron	N/A	ENSP00000621639.1

Frequencies

GnomAD3 genomes

AF:

0.0195

AC:

1286

AN:

65820

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0522

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00971

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0288

Gnomad NFE

AF:

0.000504

Gnomad OTH

AF:

0.0194

GnomAD2 exomes

AF:

0.00443

AC:

333

AN:

75160

AF XY:

0.00351

show subpopulations

Gnomad AFR exome

AF:

0.0500

Gnomad AMR exome

AF:

0.00395

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000448

Gnomad OTH exome

AF:

0.00543

GnomAD4 exome

AF:

0.00114

AC:

1581

AN:

1384694

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

711

AN XY:

683636

show subpopulations

African (AFR)

AF:

0.0364

AC:

1140

AN:

31336

American (AMR)

AF:

0.00216

AC:

AN:

36080

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25134

East Asian (EAS)

AF:

0.00

AC:

AN:

35806

South Asian (SAS)

AF:

0.000164

AC:

AN:

79190

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49178

Middle Eastern (MID)

AF:

0.00568

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

0.000106

AC:

113

AN:

1064952

Other (OTH)

AF:

0.00357

AC:

205

AN:

57382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

Heterozygous variant carriers

156

233

311

389

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.0196

AC:

1292

AN:

65916

Hom.:

Cov.:

AF XY:

0.0189

AC XY:

621

AN XY:

32818

show subpopulations

African (AFR)

AF:

0.0524

AC:

1200

AN:

22910

American (AMR)

AF:

0.00967

AC:

AN:

5892

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1286

East Asian (EAS)

AF:

0.00

AC:

AN:

2828

South Asian (SAS)

AF:

0.000829

AC:

AN:

2412

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5458

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000504

AC:

AN:

23802

Other (OTH)

AF:

0.0190

AC:

AN:

946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

123

185

246

308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00445

Hom.:

Bravo

AF:

0.00991

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Arthrogryposis multiplex congenita (1)

Arthrogryposis, distal, type 1A (1)

Nemaline Myopathy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism

(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

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

Computational scores

Splicing

Publications

Other links and lift over