9-35683243-TGGGGGG-TGGGGGGGGG

Variant names:

• chr9-35683243-T-TGGG
• rs35401252
• NM_003289.4:c.773-5_773-3dupCCC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_003289.4(TPM2):​c.773-5_773-3dupCCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000649 in 1,492,496 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00058 (0 hom.)
• Consequence: TPM2 NM_003289.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• 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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 9-35683243-T-TGGG is Benign according to our data. Variant chr9-35683243-T-TGGG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 366768.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 189 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM2	NM_003289.4	c.773-5_773-3dupCCC		splice_region_variant, intron_variant	Intron 8 of 8	ENST00000645482.3	NP_003280.2
TPM2	NM_001301226.2	c.772+1000_772+1002dupCCC		intron_variant	Intron 8 of 8		NP_001288155.1
TPM2	NM_001301227.2	c.773-5_773-3dupCCC		splice_region_variant, intron_variant	Intron 8 of 8		NP_001288156.1
TPM2	NM_213674.1	c.772+1000_772+1002dupCCC		intron_variant	Intron 8 of 8		NP_998839.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM2	ENST00000645482.3	c.773-3_773-2insCCC		splice_region_variant, intron_variant	Intron 8 of 8		NM_003289.4	ENSP00000496494.2

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 187 AN: 150428 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000592

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00173

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00174

Gnomad OTH AF: 0.000484

GnomAD3 exomes AF: 0.000461 AC: 71 AN: 154034 Hom.: 0 AF XY: 0.000431 AC XY: 35 AN XY: 81146

Gnomad AFR exome AF: 0.000359

Gnomad AMR exome AF: 0.000365

Gnomad ASJ exome AF: 0.000119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.000642

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000580 AC: 779 AN: 1341950 Hom.: 0 Cov.: 34 AF XY: 0.000588 AC XY: 390 AN XY: 663734

Gnomad4 AFR exome AF: 0.000260

Gnomad4 AMR exome AF: 0.000254

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000128

Gnomad4 FIN exome AF: 0.00168

Gnomad4 NFE exome AF: 0.000636

Gnomad4 OTH exome AF: 0.000465

GnomAD4 genome AF: 0.00126 AC: 189 AN: 150546 Hom.: 0 Cov.: 0 AF XY: 0.00122 AC XY: 90 AN XY: 73564

Gnomad4 AFR AF: 0.000640

Gnomad4 AMR AF: 0.00171

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00173

Gnomad4 NFE AF: 0.00174

Gnomad4 OTH AF: 0.000478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline Myopathy, Dominant Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arthrogryposis multiplex congenita Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

May 12, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Arthrogryposis, distal, type 1A Benign:1

Jul 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Apr 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TPM2: BS1, BS2 -

TPM2-related disorder Benign:1

Mar 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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;