chr9-35683243-T-TG

Position:

• chr9-35683243-T-TG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_003289.4(TPM2):​c.773-3dupC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 1,484,044 control chromosomes in the GnomAD database, including 61,278 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6387 hom., cov: 0)
  • Exomes 𝑓: 0.32 (54891 hom.)
• Consequence: TPM2 NM_003289.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 1.23

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 9-35683243-T-TG is Benign according to our data. Variant chr9-35683243-T-TG is described in ClinVar as [Likely_benign]. Clinvar id is 94124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM2	NM_003289.4	c.773-3dupC		splice_region_variant, intron_variant		ENST00000645482.3	NP_003280.2
TPM2	NM_001301226.2	c.772+1002dupC		intron_variant			NP_001288155.1
TPM2	NM_001301227.2	c.773-3dupC		splice_region_variant, intron_variant			NP_001288156.1
TPM2	NM_213674.1	c.772+1002dupC		intron_variant			NP_998839.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM2	ENST00000645482.3	c.773-3dupC		splice_region_variant, intron_variant			NM_003289.4	ENSP00000496494.2

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40146 AN: 150290 Hom.: 6392 Cov.: 0

Gnomad AFR AF: 0.0844

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.264

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.270

GnomAD3 exomes AF: 0.300 AC: 46173 AN: 154034 Hom.: 5997 AF XY: 0.301 AC XY: 24387 AN XY: 81146

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.330

Gnomad ASJ exome AF: 0.338

Gnomad EAS exome AF: 0.248

Gnomad SAS exome AF: 0.266

Gnomad FIN exome AF: 0.244

Gnomad NFE exome AF: 0.346

Gnomad OTH exome AF: 0.318

GnomAD4 exome AF: 0.320 AC: 426562 AN: 1333638 Hom.: 54891 Cov.: 34 AF XY: 0.319 AC XY: 210613 AN XY: 659816

Gnomad4 AFR exome AF: 0.0933

Gnomad4 AMR exome AF: 0.318

Gnomad4 ASJ exome AF: 0.324

Gnomad4 EAS exome AF: 0.217

Gnomad4 SAS exome AF: 0.267

Gnomad4 FIN exome AF: 0.245

Gnomad4 NFE exome AF: 0.338

Gnomad4 OTH exome AF: 0.309

GnomAD4 genome AF: 0.267 AC: 40138 AN: 150406 Hom.: 6387 Cov.: 0 AF XY: 0.264 AC XY: 19388 AN XY: 73458

Gnomad4 AFR AF: 0.0845

Gnomad4 AMR AF: 0.326

Gnomad4 ASJ AF: 0.356

Gnomad4 EAS AF: 0.264

Gnomad4 SAS AF: 0.274

Gnomad4 FIN AF: 0.247

Gnomad4 NFE AF: 0.359

Gnomad4 OTH AF: 0.269

Bravo AF: 0.269

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	Jan 16, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2 Other:1

not provided, no classification provided	literature only	TPM2 homepage - Leiden Muscular Dystrophy pages	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Arthrogryposis, distal, type 1A Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Nemaline Myopathy, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Arthrogryposis multiplex congenita Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs35401252; hg19: chr9-35683240;