9-35684825-CG-CGG

Variant names:

• chr9-35684825-C-CG
• rs3215700
• NM_003289.4:c.564-19dupC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_003289.4(TPM2):​c.564-19dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.619 in 1,596,748 control chromosomes in the GnomAD database, including 303,763 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29446 hom., cov: 0)
  • Exomes 𝑓: 0.62 (274317 hom.)
• Consequence: TPM2 NM_003289.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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), 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 9-35684825-C-CG is Benign according to our data. Variant chr9-35684825-C-CG is described in ClinVar as Benign. ClinVar VariationId is 94123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.688 is higher than 0.05.

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.564-19dupC		intron	N/A	NP_003280.2
	TPM2	NM_001301226.2		c.564-19dupC		intron	N/A	NP_001288155.1	Q5TCU3
	TPM2	NM_001301227.2		c.639+238dupC		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.564-19dupC		intron	N/A	ENSP00000496494.2	P07951-1
	TPM2	ENST00000378292.9	TSL:1	c.639+238dupC		intron	N/A	ENSP00000367542.3	P07951-2
	TPM2	ENST00000951580.1		c.640-80dupC		intron	N/A	ENSP00000621639.1

Frequencies

GnomAD3 genomes AF: 0.624 AC: 93834 AN: 150344 Hom.: 29415 Cov.: 0

Gnomad AFR AF: 0.596

Gnomad AMI AF: 0.558

Gnomad AMR AF: 0.628

Gnomad ASJ AF: 0.608

Gnomad EAS AF: 0.640

Gnomad SAS AF: 0.707

Gnomad FIN AF: 0.705

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.622

Gnomad OTH AF: 0.644

GnomAD4 exome AF: 0.618 AC: 893752 AN: 1446288 Hom.: 274317 Cov.: 36 AF XY: 0.620 AC XY: 446208 AN XY: 719346

African (AFR) AF: 0.587 AC: 19411 AN: 33048

American (AMR) AF: 0.620 AC: 27002 AN: 43574

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 15712 AN: 25734

East Asian (EAS) AF: 0.631 AC: 24824 AN: 39362

South Asian (SAS) AF: 0.694 AC: 59189 AN: 85238

European-Finnish (FIN) AF: 0.682 AC: 35843 AN: 52584

Middle Eastern (MID) AF: 0.649 AC: 3699 AN: 5700

European-Non Finnish (NFE) AF: 0.609 AC: 671242 AN: 1101324

Other (OTH) AF: 0.617 AC: 36830 AN: 59724

GnomAD4 genome AF: 0.624 AC: 93917 AN: 150460 Hom.: 29446 Cov.: 0 AF XY: 0.629 AC XY: 46210 AN XY: 73418

African (AFR) AF: 0.596 AC: 24313 AN: 40798

American (AMR) AF: 0.629 AC: 9516 AN: 15136

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 2109 AN: 3468

East Asian (EAS) AF: 0.640 AC: 3257 AN: 5086

South Asian (SAS) AF: 0.708 AC: 3370 AN: 4758

European-Finnish (FIN) AF: 0.705 AC: 7264 AN: 10302

Middle Eastern (MID) AF: 0.555 AC: 162 AN: 292

European-Non Finnish (NFE) AF: 0.622 AC: 42079 AN: 67634

Other (OTH) AF: 0.645 AC: 1340 AN: 2078

Alfa AF: 0.565 Hom.: 2743

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Arthrogryposis, distal, type 1A (1)

Computational scores

Source: dbNSFP v4.9

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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: COSV61406999; COSMIC: COSV61406999;