9-35685138-G-T

Variant names:

• chr9-35685138-G-T
• rs1071716
• ENST00000378292.9:c.565C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000378292.9(TPM2):​c.565C>A​(p.Arg189Arg) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM2 ENST00000378292.9 splice_region, synonymous
• Scores: Splicing: ADA: 0.04177
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.65
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000378292.9. 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.563+131C>A		intron	N/A	NP_003280.2
	TPM2	NM_001301227.2		c.565C>A	p.Arg189Arg	splice_region synonymous	Exon 6 of 9	NP_001288156.1
	TPM2	NM_213674.1		c.565C>A	p.Arg189Arg	splice_region synonymous	Exon 6 of 9	NP_998839.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM2	ENST00000378292.9	TSL:1	c.565C>A	p.Arg189Arg	splice_region synonymous	Exon 6 of 9	ENSP00000367542.3
	TPM2	ENST00000645482.3	MANE Select	c.563+131C>A		intron	N/A	ENSP00000496494.2
	TPM2	ENST00000647435.1		c.565C>A	p.Arg189Arg	splice_region synonymous	Exon 6 of 9	ENSP00000495440.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Benign	0.93
PhyloP100		5.7
PromoterAI		-0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.042
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.97		Position offset: -2

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

Other links and lift over

dbSNP: rs1071716; hg19: chr9-35685135;