rs528068364

Positions:

• chr9-35685346-GGAGT-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_003289.4(TPM2):​c.493-11_493-8del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000317 in 1,614,186 control chromosomes in the GnomAD database, including 1 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 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: TPM2 NM_003289.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.663

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 9-35685346-GGAGT-G is Benign according to our data. Variant chr9-35685346-GGAGT-G is described in ClinVar as [Likely_benign]. Clinvar id is 197751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00181 (276/152296) while in subpopulation AFR AF= 0.00628 (261/41568). AF 95% confidence interval is 0.00565. There are 0 homozygotes in gnomad4. There are 142 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 276 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM2	NM_003289.4	c.493-11_493-8del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000645482.3	NP_003280.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM2	ENST00000645482.3	c.493-11_493-8del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_003289.4	ENSP00000496494	A1

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 271 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00618

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000489 AC: 123 AN: 251438 Hom.: 0 AF XY: 0.000368 AC XY: 50 AN XY: 135892

Gnomad AFR exome AF: 0.00664

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000161 AC: 235 AN: 1461890 Hom.: 1 AF XY: 0.000132 AC XY: 96 AN XY: 727246

Gnomad4 AFR exome AF: 0.00576

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.00181 AC: 276 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74466

Gnomad4 AFR AF: 0.00628

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000781 Hom.: 0

Bravo AF: 0.00205

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 31, 2014	- -

Arthrogryposis, distal, type 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

- -

TPM2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2024

This variant is classified as 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

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: rs528068364; hg19: chr9-35685343;