ENST00000378292.9:c.773-137A>G

Variant names:

• chr9-35682300-T-C
• rs138411906
• ENST00000378292.9:c.773-137A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000378292.9(TPM2):​c.773-137A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,018,706 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (13 hom., cov: 33)
  • Exomes 𝑓: 0.013 (90 hom.)
• Consequence: TPM2 ENST00000378292.9 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.854
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• TPM2-related myopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arthrogryposis, distal, type 1A

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• congenital myopathy 23

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital myopathy

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• cap myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• digitotalar dysmorphism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Sheldon-hall syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 9-35682300-T-C is Benign according to our data. Variant chr9-35682300-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1193556.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 = 0.00976 (1484/152108) while in subpopulation NFE AF = 0.015 (1018/67994). AF 95% confidence interval is 0.0142. There are 13 homozygotes in GnomAd4. There are 717 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000378292.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM2	NM_001301226.2		c.773-137A>G		intron	N/A	NP_001288155.1	Q5TCU3
	TPM2	NM_213674.1		c.773-137A>G		intron	N/A	NP_998839.1	P07951-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM2	ENST00000378292.9	TSL:1	c.773-137A>G		intron	N/A	ENSP00000367542.3	P07951-2
	TPM2	ENST00000951578.1		c.*859A>G		3_prime_UTR	Exon 9 of 9	ENSP00000621637.1
	TPM2	ENST00000951577.1		c.*859A>G		3_prime_UTR	Exon 9 of 9	ENSP00000621636.1

Frequencies

GnomAD3 genomes AF: 0.00976 AC: 1484 AN: 151990 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00300

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00687

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00459

Gnomad FIN AF: 0.0161

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.0105

GnomAD4 exome AF: 0.0128 AC: 11078 AN: 866598 Hom.: 90 Cov.: 12 AF XY: 0.0126 AC XY: 5646 AN XY: 446450

African (AFR) AF: 0.00246 AC: 53 AN: 21570

American (AMR) AF: 0.00449 AC: 157 AN: 34994

Ashkenazi Jewish (ASJ) AF: 0.00473 AC: 103 AN: 21754

East Asian (EAS) AF: 0.000120 AC: 4 AN: 33442

South Asian (SAS) AF: 0.00491 AC: 335 AN: 68234

European-Finnish (FIN) AF: 0.0182 AC: 682 AN: 37396

Middle Eastern (MID) AF: 0.00351 AC: 11 AN: 3134

European-Non Finnish (NFE) AF: 0.0154 AC: 9318 AN: 605592

Other (OTH) AF: 0.0103 AC: 415 AN: 40482

GnomAD4 genome AF: 0.00976 AC: 1484 AN: 152108 Hom.: 13 Cov.: 33 AF XY: 0.00964 AC XY: 717 AN XY: 74348

African (AFR) AF: 0.00299 AC: 124 AN: 41480

American (AMR) AF: 0.00686 AC: 105 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 21 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00459 AC: 22 AN: 4794

European-Finnish (FIN) AF: 0.0161 AC: 170 AN: 10578

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0150 AC: 1018 AN: 67994

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.00770 Hom.: 3

Bravo AF: 0.00824

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.26
DANN	Benign	0.55
PhyloP100		-0.85
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs138411906; hg19: chr9-35682297;