rs1998308

Variant names:

• chr9-35683885-A-T
• rs1998308
• NM_003289.4:c.772+361T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003289.4(TPM2):​c.772+361T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 152,062 control chromosomes in the GnomAD database, including 27,602 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.60 (27602 hom., cov: 32)
• Consequence: TPM2 NM_003289.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.143
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.647 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM2	NM_003289.4	MANE Select	c.772+361T>A		intron	N/A	NP_003280.2
	TPM2	NM_001301226.2		c.772+361T>A		intron	N/A	NP_001288155.1
	TPM2	NM_001301227.2		c.772+361T>A		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.772+361T>A		intron	N/A	ENSP00000496494.2
	TPM2	ENST00000378292.9	TSL:1	c.772+361T>A		intron	N/A	ENSP00000367542.3
	TPM2	ENST00000329305.6	TSL:2	c.772+361T>A		intron	N/A	ENSP00000367541.1

Frequencies

GnomAD3 genomes AF: 0.598 AC: 90800 AN: 151944 Hom.: 27566 Cov.: 32

Gnomad AFR AF: 0.533

Gnomad AMI AF: 0.667

Gnomad AMR AF: 0.655

Gnomad ASJ AF: 0.621

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.544

Gnomad MID AF: 0.685

Gnomad NFE AF: 0.652

Gnomad OTH AF: 0.597

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.598 AC: 90882 AN: 152062 Hom.: 27602 Cov.: 32 AF XY: 0.593 AC XY: 44048 AN XY: 74340

African (AFR) AF: 0.533 AC: 22105 AN: 41454

American (AMR) AF: 0.655 AC: 10007 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.621 AC: 2154 AN: 3466

East Asian (EAS) AF: 0.324 AC: 1680 AN: 5190

South Asian (SAS) AF: 0.584 AC: 2814 AN: 4816

European-Finnish (FIN) AF: 0.544 AC: 5747 AN: 10566

Middle Eastern (MID) AF: 0.678 AC: 198 AN: 292

European-Non Finnish (NFE) AF: 0.652 AC: 44315 AN: 67980

Other (OTH) AF: 0.595 AC: 1256 AN: 2110

Alfa AF: 0.622 Hom.: 3655

Bravo AF: 0.602

Asia WGS AF: 0.467 AC: 1626 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.2
DANN	Benign	0.42
PhyloP100		0.14
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: rs1998308; hg19: chr9-35683882; COSMIC: COSV61406040; COSMIC: COSV61406040;