2-178740453-C-T

Position:

chr2-178740453-C-T

Variant summary

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

The NM_001267550.2(TTN):c.12780G>A(p.Ala4260Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,613,234 control chromosomes in the GnomAD database, including 20,284 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A4260A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.16 ( 2230 hom., cov: 32)

Exomes 𝑓: 0.14 ( 18054 hom. )

Consequence

TTN
NM_001267550.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: -0.0990

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:):

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=-0.83).

BP6

Variant 2-178740453-C-T is Benign according to our data. Variant chr2-178740453-C-T is described in ClinVar as [Benign]. Clinvar id is 47830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178740453-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.099 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.12780G>A	p.Ala4260Ala	synonymous_variant	48/363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.12780G>A	p.Ala4260Ala	synonymous_variant	48/363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.155

AC:

23557

AN:

151956

Hom.:

2226

Cov.:

show subpopulations

Gnomad AFR

AF:

0.159

Gnomad AMI

AF:

0.455

Gnomad AMR

AF:

0.153

Gnomad ASJ

AF:

0.120

Gnomad EAS

AF:

0.462

Gnomad SAS

AF:

0.205

Gnomad FIN

AF:

0.0958

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.133

Gnomad OTH

AF:

0.156

GnomAD3 exomes

AF:

0.164

AC:

40576

AN:

247814

Hom.:

4352

AF XY:

0.165

AC XY:

22163

AN XY:

134410

show subpopulations

Gnomad AFR exome

AF:

0.160

Gnomad AMR exome

AF:

0.142

Gnomad ASJ exome

AF:

0.114

Gnomad EAS exome

AF:

0.462

Gnomad SAS exome

AF:

0.207

Gnomad FIN exome

AF:

0.0946

Gnomad NFE exome

AF:

0.130

Gnomad OTH exome

AF:

0.152

GnomAD4 exome

AF:

0.144

AC:

210847

AN:

1461160

Hom.:

18054

Cov.:

AF XY:

0.146

AC XY:

105862

AN XY:

726818

show subpopulations

Gnomad4 AFR exome

AF:

0.162

Gnomad4 AMR exome

AF:

0.144

Gnomad4 ASJ exome

AF:

0.115

Gnomad4 EAS exome

AF:

0.472

Gnomad4 SAS exome

AF:

0.203

Gnomad4 FIN exome

AF:

0.0916

Gnomad4 NFE exome

AF:

0.130

Gnomad4 OTH exome

AF:

0.154

GnomAD4 genome

AF:

0.155

AC:

23575

AN:

152074

Hom.:

2230

Cov.:

AF XY:

0.157

AC XY:

11649

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.159

Gnomad4 AMR

AF:

0.153

Gnomad4 ASJ

AF:

0.120

Gnomad4 EAS

AF:

0.461

Gnomad4 SAS

AF:

0.205

Gnomad4 FIN

AF:

0.0958

Gnomad4 NFE

AF:

0.133

Gnomad4 OTH

AF:

0.161

Alfa

AF:

0.133

Hom.:

512

EpiCase

AF:

0.133

EpiControl

AF:

0.138

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 01, 2012	Ala4022Ala 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 14.6% (470/3210) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS/; rs746578). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2012	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 18, 2019

- -

Early-onset myopathy with fatal cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 17, 2022

- -

Myopathy, myofibrillar, 9, with early respiratory failure

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

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2015

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

-0.83

CADD

Benign

2.3

DANN

Benign

0.78

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