rs2562849

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001267550.2(TTN):c.36203-9T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 1,608,246 control chromosomes in the GnomAD database, including 743 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 76 hom., cov: 31)

Exomes 𝑓: 0.026 ( 667 hom. )

Consequence

TTN
NM_001267550.2 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0005297

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.63

Variant links:

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN links:

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

TTN-AS1 links:

LOC124906100 (HGNC:):

LOC124906100 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 2-178664546-A-G is Benign according to our data. Variant chr2-178664546-A-G is described in ClinVar as [Benign]. Clinvar id is 413235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178664546-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0882 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.36203-9T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000589042.5
LOC124906100	XR_007087318.1 linkuse as main transcript	n.2185+20045A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.36203-9T>C		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.502+66865A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0233

AC:

3540

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00490

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.0252

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.0949

Gnomad SAS

AF:

0.0315

Gnomad FIN

AF:

0.0453

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0247

Gnomad OTH

AF:

0.0234

GnomAD3 exomes

AF:

0.0335

AC:

7924

AN:

236650

Hom.:

204

AF XY:

0.0326

AC XY:

4239

AN XY:

129948

show subpopulations

Gnomad AFR exome

AF:

0.00522

Gnomad AMR exome

AF:

0.0353

Gnomad ASJ exome

AF:

0.0155

Gnomad EAS exome

AF:

0.103

Gnomad SAS exome

AF:

0.0289

Gnomad FIN exome

AF:

0.0478

Gnomad NFE exome

AF:

0.0254

Gnomad OTH exome

AF:

0.0312

GnomAD4 exome

AF:

0.0260

AC:

37787

AN:

1456022

Hom.:

667

Cov.:

AF XY:

0.0261

AC XY:

18911

AN XY:

724364

show subpopulations

Gnomad4 AFR exome

AF:

0.00468

Gnomad4 AMR exome

AF:

0.0331

Gnomad4 ASJ exome

AF:

0.0152

Gnomad4 EAS exome

AF:

0.0912

Gnomad4 SAS exome

AF:

0.0283

Gnomad4 FIN exome

AF:

0.0492

Gnomad4 NFE exome

AF:

0.0230

Gnomad4 OTH exome

AF:

0.0264

GnomAD4 genome

AF:

0.0233

AC:

3540

AN:

152224

Hom.:

Cov.:

AF XY:

0.0241

AC XY:

1790

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.00489

Gnomad4 AMR

AF:

0.0252

Gnomad4 ASJ

AF:

0.0196

Gnomad4 EAS

AF:

0.0951

Gnomad4 SAS

AF:

0.0315

Gnomad4 FIN

AF:

0.0453

Gnomad4 NFE

AF:

0.0247

Gnomad4 OTH

AF:

0.0232

Alfa

AF:

0.0160

Hom.:

Bravo

AF:

0.0209

Asia WGS

AF:

0.0480

AC:

167

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 18, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Autosomal recessive limb-girdle muscular dystrophy type 2J

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Early-onset myopathy with fatal cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Tibial muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Myopathy, myofibrillar, 9, with early respiratory failure

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

Cadd

Benign

Dann

Benign

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00053

dbscSNV1_RF

Benign

0.084

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

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

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