9-35684825-CG-CGGG

Variant names:

• chr9-35684825-C-CGG
• rs3215700
• NM_003289.4:c.564-20_564-19dupCC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.39
• Publications: 6 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: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	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
	TPM2	NM_001301227.2		c.639+237_639+238dupCC		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.564-20_564-19dupCC		intron	N/A	ENSP00000496494.2
	TPM2	ENST00000378292.9	TSL:1	c.639+237_639+238dupCC		intron	N/A	ENSP00000367542.3
	TPM2	ENST00000471212.5	TSL:2	n.959_960dupCC		non_coding_transcript_exon	Exon 6 of 7

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 288 AN: 150518 Hom.: 4 Cov.: 0

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.: 10 Cov.: 36 AF XY: 0.00191 AC XY: 1371 AN XY: 717934

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

African (AFR) AF: 0.000697 AC: 23 AN: 32996

American (AMR) AF: 0.00209 AC: 91 AN: 43534

Ashkenazi Jewish (ASJ) AF: 0.00117 AC: 30 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: 8 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.

GnomAD4 genome AF: 0.00193 AC: 291 AN: 150634 Hom.: 4 Cov.: 0 AF XY: 0.00201 AC XY: 148 AN XY: 73496

African (AFR) AF: 0.000661 AC: 27 AN: 40876

American (AMR) AF: 0.00172 AC: 26 AN: 15156

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.0120 AC: 61 AN: 5084

South Asian (SAS) AF: 0.00105 AC: 5 AN: 4762

European-Finnish (FIN) AF: 0.00698 AC: 72 AN: 10308

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00123 AC: 83 AN: 67698

Other (OTH) AF: 0.00625 AC: 13 AN: 2080

Alfa AF: 0.00178 Hom.: 2743

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Apr 06, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arthrogryposis, distal, type 1A Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs3215700; hg19: chr9-35684822; COSMIC: COSV100253214; COSMIC: COSV100253214;