Genetic Variant TPM2:c.773-3delC (chr9-35683243-TG-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_003289.4(TPM2):c.773-3delC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000957 in 1,493,662 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00010 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000095 ( 0 hom. )

Consequence

TPM2
NM_003289.4 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.23

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP6

Variant 9-35683243-TG-T is Benign according to our data. Variant chr9-35683243-TG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167742.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}. Variant chr9-35683243-TG-T is described in Lovd as [Benign]. Variant chr9-35683243-TG-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TPM2	NM_003289.4 link	c.773-3delC	splice_region_variant, intron_variant	Intron 8 of 8	ENST00000645482.3	NP_003280.2	P07951-1
TPM2	NM_001301226.2 link	c.772+1002delC	intron_variant	Intron 8 of 8		NP_001288155.1	Q5TCU3V9HW25
TPM2	NM_001301227.2 link	c.773-3delC	splice_region_variant, intron_variant	Intron 8 of 8		NP_001288156.1	A7XZE4V9HW25
TPM2	NM_213674.1 link	c.772+1002delC	intron_variant	Intron 8 of 8		NP_998839.1	P07951-2V9HW25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM2	ENST00000645482.3 link	c.773-3delC		splice_region_variant, intron_variant	Intron 8 of 8		NM_003289.4	ENSP00000496494.2		P07951-1

Frequencies

GnomAD3 genomes

AF:

0.0000997

AC:

AN:

150450

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000493

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000198

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000630

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000886

Gnomad OTH

AF:

0.000484

GnomAD3 exomes

AF:

0.000195

AC:

AN:

154034

Hom.:

AF XY:

0.000197

AC XY:

AN XY:

81146

show subpopulations

Gnomad AFR exome

AF:

0.000120

Gnomad AMR exome

AF:

0.000243

Gnomad ASJ exome

AF:

0.000119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000662

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000118

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000953

AC:

128

AN:

1343094

Hom.:

Cov.:

AF XY:

0.0000963

AC XY:

AN XY:

664250

show subpopulations

Gnomad4 AFR exome

AF:

0.0000975

Gnomad4 AMR exome

AF:

0.000254

Gnomad4 ASJ exome

AF:

0.0000409

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000690

Gnomad4 FIN exome

AF:

0.0000206

Gnomad4 NFE exome

AF:

0.0000447

Gnomad4 OTH exome

AF:

0.000197

GnomAD4 genome

AF:

0.0000996

AC:

AN:

150568

Hom.:

Cov.:

AF XY:

0.0000951

AC XY:

AN XY:

73572

show subpopulations

Gnomad4 AFR

AF:

0.0000492

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000630

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000886

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000165

Hom.:

621

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Apr 04, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arthrogryposis, distal, type 1A

Benign:1

Nov 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

9-35683243-TGGGGGG-TGGGGG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over