rs1883084

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001267550.2(TTN):c.13218C>T(p.Ala4406Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0529 in 1,613,746 control chromosomes in the GnomAD database, including 3,850 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.051 ( 382 hom., cov: 32)

Exomes 𝑓: 0.053 ( 3468 hom. )

Consequence

TTN
NM_001267550.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.844

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 2-178740015-G-A is Benign according to our data. Variant chr2-178740015-G-A is described in ClinVar as [Benign]. Clinvar id is 47836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178740015-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.844 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.13218C>T	p.Ala4406Ala	synonymous_variant	Exon 48 of 363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.13218C>T	p.Ala4406Ala	synonymous_variant	Exon 48 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.0507

AC:

7708

AN:

152038

Hom.:

381

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0141

Gnomad AMI

AF:

0.0473

Gnomad AMR

AF:

0.137

Gnomad ASJ

AF:

0.0486

Gnomad EAS

AF:

0.188

Gnomad SAS

AF:

0.0231

Gnomad FIN

AF:

0.0512

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0454

Gnomad OTH

AF:

0.0469

GnomAD3 exomes

AF:

0.0799

AC:

19858

AN:

248418

Hom.:

1721

AF XY:

0.0704

AC XY:

9491

AN XY:

134746

show subpopulations

Gnomad AFR exome

AF:

0.0137

Gnomad AMR exome

AF:

0.241

Gnomad ASJ exome

AF:

0.0485

Gnomad EAS exome

AF:

0.208

Gnomad SAS exome

AF:

0.0191

Gnomad FIN exome

AF:

0.0524

Gnomad NFE exome

AF:

0.0445

Gnomad OTH exome

AF:

0.0674

GnomAD4 exome

AF:

0.0531

AC:

77589

AN:

1461590

Hom.:

3468

Cov.:

AF XY:

0.0513

AC XY:

37299

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.0126

Gnomad4 AMR exome

AF:

0.229

Gnomad4 ASJ exome

AF:

0.0474

Gnomad4 EAS exome

AF:

0.189

Gnomad4 SAS exome

AF:

0.0201

Gnomad4 FIN exome

AF:

0.0546

Gnomad4 NFE exome

AF:

0.0453

Gnomad4 OTH exome

AF:

0.0519

GnomAD4 genome

AF:

0.0507

AC:

7711

AN:

152156

Hom.:

382

Cov.:

AF XY:

0.0523

AC XY:

3891

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.0140

Gnomad4 AMR

AF:

0.138

Gnomad4 ASJ

AF:

0.0486

Gnomad4 EAS

AF:

0.189

Gnomad4 SAS

AF:

0.0225

Gnomad4 FIN

AF:

0.0512

Gnomad4 NFE

AF:

0.0454

Gnomad4 OTH

AF:

0.0455

Alfa

AF:

0.0450

Hom.:

100

Bravo

AF:

0.0616

Asia WGS

AF:

0.0770

AC:

265

AN:

3476

EpiCase

AF:

0.0407

EpiControl

AF:

0.0431

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 26, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ala4168Ala in exon 45B of TTN: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 4.5% (299/6620) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS/; rs1883084). -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 19, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal recessive limb-girdle muscular dystrophy type 2J

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early-onset myopathy with fatal cardiomyopathy

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Tibial muscular dystrophy

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myopathy, myofibrillar, 9, with early respiratory failure

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Apr 20, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.36

DANN

Benign

0.84

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

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