rs1243872

Variant names:

• chr9-35686410-T-G
• rs1243872
• NM_003289.4:c.241-630A>C

Variant summary

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

The NM_003289.4(TPM2):​c.241-630A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.485 in 158,826 control chromosomes in the GnomAD database, including 18,842 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 0.49 (18149 hom., cov: 30)
  • Exomes 𝑓: 0.44 (693 hom.)
• Consequence: TPM2 NM_003289.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.557
• Publications: 14 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM2	NM_003289.4	c.241-630A>C		intron_variant	Intron 2 of 8	ENST00000645482.3	NP_003280.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM2	ENST00000645482.3	c.241-630A>C		intron_variant	Intron 2 of 8		NM_003289.4	ENSP00000496494.2

Frequencies

GnomAD3 genomes AF: 0.487 AC: 73965 AN: 151814 Hom.: 18129 Cov.: 30

Gnomad AFR AF: 0.554

Gnomad AMI AF: 0.571

Gnomad AMR AF: 0.430

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.554

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.459

Gnomad OTH AF: 0.500

GnomAD4 exome AF: 0.436 AC: 3007 AN: 6894 Hom.: 693 Cov.: 0 AF XY: 0.432 AC XY: 1574 AN XY: 3646

African (AFR) AF: 0.542 AC: 13 AN: 24

American (AMR) AF: 0.378 AC: 647 AN: 1712

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 10 AN: 20

East Asian (EAS) AF: 0.554 AC: 93 AN: 168

South Asian (SAS) AF: 0.461 AC: 332 AN: 720

European-Finnish (FIN) AF: 0.383 AC: 23 AN: 60

Middle Eastern (MID) AF: 0.500 AC: 4 AN: 8

European-Non Finnish (NFE) AF: 0.453 AC: 1767 AN: 3900

Other (OTH) AF: 0.418 AC: 118 AN: 282

GnomAD4 genome AF: 0.487 AC: 74026 AN: 151932 Hom.: 18149 Cov.: 30 AF XY: 0.486 AC XY: 36122 AN XY: 74268

African (AFR) AF: 0.554 AC: 22944 AN: 41440

American (AMR) AF: 0.430 AC: 6554 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 1549 AN: 3468

East Asian (EAS) AF: 0.555 AC: 2855 AN: 5148

South Asian (SAS) AF: 0.491 AC: 2364 AN: 4816

European-Finnish (FIN) AF: 0.461 AC: 4864 AN: 10546

Middle Eastern (MID) AF: 0.459 AC: 134 AN: 292

European-Non Finnish (NFE) AF: 0.459 AC: 31185 AN: 67948

Other (OTH) AF: 0.502 AC: 1056 AN: 2104

Alfa AF: 0.469 Hom.: 17675

Bravo AF: 0.491

Asia WGS AF: 0.555 AC: 1929 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.0
DANN	Benign	0.78
PhyloP100		-0.56
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: rs1243872; hg19: chr9-35686407;