2-178752043-GA-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_133379.5(TTN):c.10361-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.69 ( 33400 hom., cov: 0)

Exomes 𝑓: 0.45 ( 13505 hom. )

Failed GnomAD Quality Control

Consequence

TTN
NM_133379.5 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2B:5

Conservation

PhyloP100: 2.56

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 2-178752043-GA-G is Benign according to our data. Variant chr2-178752043-GA-G is described in ClinVar as [Likely_benign]. Clinvar id is 47724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178752043-GA-G is described in Lovd as [Benign]. Variant chr2-178752043-GA-G is described in Lovd as [Benign]. Variant chr2-178752043-GA-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.11311+1080delT		intron_variant	Intron 47 of 362	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7
TTN	NM_133379.5 link	c.10361-5delT		splice_region_variant, intron_variant	Intron 45 of 45	ENST00000360870.10	NP_596870.2	Q8WZ42-6Q7Z3B7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.11311+1080delT		intron_variant	Intron 47 of 362	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7
TTN	ENST00000360870.10 link	c.10361-5delT		splice_region_variant, intron_variant	Intron 45 of 45	5	NM_133379.5	ENSP00000354117.4		Q8WZ42-6

Frequencies

GnomAD3 genomes

AF:

0.692

AC:

97487

AN:

140786

Hom.:

33390

Cov.:

show subpopulations

Gnomad AFR

AF:

0.762

Gnomad AMI

AF:

0.808

Gnomad AMR

AF:

0.645

Gnomad ASJ

AF:

0.555

Gnomad EAS

AF:

0.913

Gnomad SAS

AF:

0.647

Gnomad FIN

AF:

0.706

Gnomad MID

AF:

0.582

Gnomad NFE

AF:

0.653

Gnomad OTH

AF:

0.658

GnomAD4 exome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.454

AC:

564297

AN:

1243988

Hom.:

13505

Cov.:

AF XY:

0.453

AC XY:

281815

AN XY:

622722

show subpopulations

Gnomad4 AFR exome

AF:

0.484

Gnomad4 AMR exome

AF:

0.447

Gnomad4 ASJ exome

AF:

0.404

Gnomad4 EAS exome

AF:

0.506

Gnomad4 SAS exome

AF:

0.439

Gnomad4 FIN exome

AF:

0.470

Gnomad4 NFE exome

AF:

0.453

Gnomad4 OTH exome

AF:

0.453

GnomAD4 genome

AF:

0.692

AC:

97520

AN:

140838

Hom.:

33400

Cov.:

AF XY:

0.693

AC XY:

47224

AN XY:

68180

show subpopulations

Gnomad4 AFR

AF:

0.762

Gnomad4 AMR

AF:

0.645

Gnomad4 ASJ

AF:

0.555

Gnomad4 EAS

AF:

0.913

Gnomad4 SAS

AF:

0.646

Gnomad4 FIN

AF:

0.706

Gnomad4 NFE

AF:

0.653

Gnomad4 OTH

AF:

0.661

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 20, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

10361-5delT in intron 45 of TTN: This variant is not expected to have clinical s ignificance because it is located outside the conserved +/- 1, 2 region of the s plicing consensus sequence and as part of a polyT stretch. This variant has bee n reported in dbSNP (rs66641728) without frequency information. 10361-5delT in intron 45 of TTN (rs66641728; allele frequency = n/a) -

not provided

Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1G

Uncertain:1

Sep 26, 2015

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 9

Uncertain:1

Sep 26, 2015

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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