9-35683243-TGGGGGG-TGGGGGGGGG

Variant names:

• chr9-35683243-T-TGGG
• rs35401252
• NM_003289.4:c.773-5_773-3dupCCC

Variant summary

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

The NM_003289.4(TPM2):​c.773-5_773-3dupCCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000649 in 1,492,496 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00058 (0 hom.)
• Consequence: TPM2 NM_003289.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 1.23
• Publications: 10 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 9-35683243-T-TGGG is Benign according to our data. Variant chr9-35683243-T-TGGG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 366768.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM2	NM_003289.4	MANE Select	c.773-5_773-3dupCCC		splice_region intron	N/A	NP_003280.2
	TPM2	NM_001301226.2		c.772+1000_772+1002dupCCC		intron	N/A	NP_001288155.1	Q5TCU3
	TPM2	NM_001301227.2		c.773-5_773-3dupCCC		splice_region intron	N/A	NP_001288156.1	A7XZE4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM2	ENST00000645482.3	MANE Select	c.773-3_773-2insCCC		splice_region intron	N/A	ENSP00000496494.2	P07951-1
	TPM2	ENST00000378292.9	TSL:1	c.772+1002_772+1003insCCC		intron	N/A	ENSP00000367542.3	P07951-2
	TPM2	ENST00000951580.1		c.788-3_788-2insCCC		splice_region intron	N/A	ENSP00000621639.1

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 187 AN: 150428 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000592

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00173

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00174

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.000461 AC: 71 AN: 154034 AF XY: 0.000431

Gnomad AFR exome AF: 0.000359

Gnomad AMR exome AF: 0.000365

Gnomad ASJ exome AF: 0.000119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.000642

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000580 AC: 779 AN: 1341950 Hom.: 0 Cov.: 34 AF XY: 0.000588 AC XY: 390 AN XY: 663734

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

African (AFR) AF: 0.000260 AC: 8 AN: 30762

American (AMR) AF: 0.000254 AC: 9 AN: 35490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24480

East Asian (EAS) AF: 0.00 AC: 0 AN: 35382

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 78308

European-Finnish (FIN) AF: 0.00168 AC: 81 AN: 48342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5554

European-Non Finnish (NFE) AF: 0.000636 AC: 654 AN: 1027766

Other (OTH) AF: 0.000465 AC: 26 AN: 55866

⚠️ 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.

GnomAD4 genome AF: 0.00126 AC: 189 AN: 150546 Hom.: 0 Cov.: 0 AF XY: 0.00122 AC XY: 90 AN XY: 73564

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

African (AFR) AF: 0.000640 AC: 26 AN: 40654

American (AMR) AF: 0.00171 AC: 26 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.00 AC: 0 AN: 4762

European-Finnish (FIN) AF: 0.00173 AC: 18 AN: 10404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00174 AC: 118 AN: 67672

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000882 Hom.: 621

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Arthrogryposis multiplex congenita (1)
-	-	1	Arthrogryposis, distal, type 1A (1)
-	1	-	Nemaline Myopathy, Dominant (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	TPM2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=94/6	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35401252; hg19: chr9-35683240;