rs11998

Variant names:

• chr9-35682299-T-A
• rs11998
• ENST00000378292.9:c.773-136A>T

Your query was ambiguous. Multiple possible variants found:

• chr9-35682299-T-A
• chr9-35682299-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_213674.1(TPM2):​c.773-136A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 1,043,166 control chromosomes in the GnomAD database, including 205,904 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27626 hom., cov: 31)
  • Exomes 𝑓: 0.63 (178278 hom.)
• Consequence: TPM2 NM_213674.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.830
• Publications: 3 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• congenital myopathy 23

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, 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=-0.91).
• BP6: Variant 9-35682299-T-A is Benign according to our data. Variant chr9-35682299-T-A is described in ClinVar as Benign. ClinVar VariationId is 1269529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.647 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213674.1. 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.773-136A>T		intron	N/A	NP_001288155.1	Q5TCU3
	TPM2	NM_213674.1		c.773-136A>T		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.773-136A>T		intron	N/A	ENSP00000367542.3	P07951-2
	TPM2	ENST00000951578.1		c.*860A>T		3_prime_UTR	Exon 9 of 9	ENSP00000621637.1
	TPM2	ENST00000951577.1		c.*860A>T		3_prime_UTR	Exon 9 of 9	ENSP00000621636.1

Frequencies

GnomAD3 genomes AF: 0.598 AC: 90835 AN: 151848 Hom.: 27591 Cov.: 31

Gnomad AFR AF: 0.534

Gnomad AMI AF: 0.665

Gnomad AMR AF: 0.655

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.545

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.652

Gnomad OTH AF: 0.598

GnomAD4 exome AF: 0.627 AC: 558587 AN: 891200 Hom.: 178278 Cov.: 12 AF XY: 0.626 AC XY: 286759 AN XY: 457978

African (AFR) AF: 0.542 AC: 11903 AN: 21942

American (AMR) AF: 0.693 AC: 24291 AN: 35060

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 13792 AN: 21976

East Asian (EAS) AF: 0.296 AC: 9922 AN: 33504

South Asian (SAS) AF: 0.589 AC: 40556 AN: 68834

European-Finnish (FIN) AF: 0.552 AC: 21172 AN: 38386

Middle Eastern (MID) AF: 0.672 AC: 2168 AN: 3226

European-Non Finnish (NFE) AF: 0.653 AC: 409069 AN: 626908

Other (OTH) AF: 0.622 AC: 25714 AN: 41364

GnomAD4 genome AF: 0.598 AC: 90915 AN: 151966 Hom.: 27626 Cov.: 31 AF XY: 0.593 AC XY: 44085 AN XY: 74288

African (AFR) AF: 0.535 AC: 22147 AN: 41428

American (AMR) AF: 0.655 AC: 10026 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 2155 AN: 3466

East Asian (EAS) AF: 0.324 AC: 1665 AN: 5146

South Asian (SAS) AF: 0.585 AC: 2814 AN: 4814

European-Finnish (FIN) AF: 0.545 AC: 5753 AN: 10552

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.652 AC: 44295 AN: 67948

Other (OTH) AF: 0.596 AC: 1258 AN: 2110

Alfa AF: 0.509 Hom.: 1417

Bravo AF: 0.602

Asia WGS AF: 0.465 AC: 1617 AN: 3476

ClinVar

ClinVar submissions

Significance: 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	-0.91
CADD	Benign	0.16
DANN	Benign	0.62
PhyloP100		-0.83
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11998; hg19: chr9-35682296;