NM_003289.4:c.773-6_773-3dupCCCC

Variant names:

• chr9-35683243-T-TGGGG
• rs35401252
• NM_003289.4:c.773-6_773-3dupCCCC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003289.4(TPM2):​c.773-6_773-3dupCCCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000744 in 1,343,392 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: TPM2 NM_003289.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23
• Publications: 0 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), 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM2	NM_003289.4	MANE Select	c.773-6_773-3dupCCCC		splice_region intron	N/A	NP_003280.2
	TPM2	NM_001301226.2		c.772+999_772+1002dupCCCC		intron	N/A	NP_001288155.1
	TPM2	NM_001301227.2		c.773-6_773-3dupCCCC		splice_region intron	N/A	NP_001288156.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM2	ENST00000645482.3	MANE Select	c.773-3_773-2insCCCC		splice_region intron	N/A	ENSP00000496494.2
	TPM2	ENST00000378292.9	TSL:1	c.772+1002_772+1003insCCCC		intron	N/A	ENSP00000367542.3
	TPM2	ENST00000329305.6	TSL:2	c.772+1002_772+1003insCCCC		intron	N/A	ENSP00000367541.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 7.44e-7 AC: 1 AN: 1343392 Hom.: 0 Cov.: 34 AF XY: 0.00000151 AC XY: 1 AN XY: 664396

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

African (AFR) AF: 0.00 AC: 0 AN: 30778

American (AMR) AF: 0.00 AC: 0 AN: 35502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24482

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 78308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48500

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

European-Non Finnish (NFE) AF: 9.72e-7 AC: 1 AN: 1028986

Other (OTH) AF: 0.00 AC: 0 AN: 55900

⚠️ 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 Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2

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;