rs41312812

chr9-35685576-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003289.4(TPM2):c.375-25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00958 in 1,614,122 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (2 hom., cov: 32)
  • Exomes 𝑓: 0.010 (99 hom.)
• Consequence: TPM2 NM_003289.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.846

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 9-35685576-G-A is Benign according to our data. Variant chr9-35685576-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00592 (901/152242) while in subpopulation NFE AF= 0.0106 (722/67994). AF 95% confidence interval is 0.00998. There are 2 homozygotes in gnomad4. There are 401 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 901 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM2	NM_003289.4	c.375-25C>T		intron_variant		ENST00000645482.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM2	ENST00000645482.3	c.375-25C>T		intron_variant			NM_003289.4	A1

Frequencies

GnomAD3 genomes AF: 0.00592 AC: 901 AN: 152124 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00677 AC: 1702 AN: 251466 Hom.: 12 AF XY: 0.00679 AC XY: 923 AN XY: 135906

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00431

Gnomad FIN exome AF: 0.00499

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00996 AC: 14567 AN: 1461880 Hom.: 99 Cov.: 35 AF XY: 0.00982 AC XY: 7141 AN XY: 727242

Gnomad4 AFR exome AF: 0.00185

Gnomad4 AMR exome AF: 0.00311

Gnomad4 ASJ exome AF: 0.00130

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00421

Gnomad4 FIN exome AF: 0.00571

Gnomad4 NFE exome AF: 0.0118

Gnomad4 OTH exome AF: 0.00778

GnomAD4 genome AF: 0.00592 AC: 901 AN: 152242 Hom.: 2 Cov.: 32 AF XY: 0.00539 AC XY: 401 AN XY: 74452

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00396

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00681 Hom.: 1

Bravo AF: 0.00574

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	3.6
Dann	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41312812; hg19: chr9-35685573;