2-178746240-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_133379.5(TTN):c.16160G>A(p.Cys5387Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,612,668 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 8 hom. )

Consequence

TTN
NM_133379.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.73

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0126847625).

BP6

Variant 2-178746240-C-T is Benign according to our data. Variant chr2-178746240-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 47795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178746240-C-T is described in Lovd as [Benign]. Variant chr2-178746240-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00253 (385/152092) while in subpopulation NFE AF= 0.00374 (254/67932). AF 95% confidence interval is 0.00336. There are 1 homozygotes in gnomad4. There are 191 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_133379.5 link	c.16160G>A	p.Cys5387Tyr	missense_variant	Exon 46 of 46	ENST00000360870.10	NP_596870.2	Q8WZ42-6Q7Z3B7
TTN	NM_001267550.2 link	c.11312-4319G>A		intron_variant	Intron 47 of 362	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000360870.10 link	c.16160G>A	p.Cys5387Tyr	missense_variant	Exon 46 of 46	5	NM_133379.5	ENSP00000354117.4		Q8WZ42-6
TTN	ENST00000589042.5 link	c.11312-4319G>A		intron_variant	Intron 47 of 362	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.00253

AC:

385

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00302

Gnomad ASJ

AF:

0.00289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.00396

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00374

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00300

AC:

747

AN:

249308

Hom.:

AF XY:

0.00289

AC XY:

390

AN XY:

134770

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.00166

Gnomad ASJ exome

AF:

0.00530

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000722

Gnomad FIN exome

AF:

0.00471

Gnomad NFE exome

AF:

0.00439

Gnomad OTH exome

AF:

0.00264

GnomAD4 exome

AF:

0.00297

AC:

4331

AN:

1460576

Hom.:

Cov.:

AF XY:

0.00300

AC XY:

2177

AN XY:

726600

show subpopulations

Gnomad4 AFR exome

AF:

0.000509

Gnomad4 AMR exome

AF:

0.00166

Gnomad4 ASJ exome

AF:

0.00364

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000847

Gnomad4 FIN exome

AF:

0.00415

Gnomad4 NFE exome

AF:

0.00328

Gnomad4 OTH exome

AF:

0.00287

GnomAD4 genome

AF:

0.00253

AC:

385

AN:

152092

Hom.:

Cov.:

AF XY:

0.00257

AC XY:

191

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.000482

Gnomad4 AMR

AF:

0.00302

Gnomad4 ASJ

AF:

0.00289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.00396

Gnomad4 NFE

AF:

0.00374

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00364

Hom.:

Bravo

AF:

0.00232

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.00291

AC:

353

Asia WGS

AF:

0.000578

AC:

AN:

3476

EpiCase

AF:

0.00508

EpiControl

AF:

0.00522

ClinVar

Significance: Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:9

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 26, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 15, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTN: BP4, BS2 -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:3

Feb 10, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Cys5387Tyr in exon 45A of TTN: This variant is not expected to have clinical s ignificance because it has been identified in 0.4% (28/7016) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS; dbSNP rs72648913). -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 19, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TTN-related disorder

Benign:1

Aug 13, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hypertrophic cardiomyopathy

Benign:1

Genetics and Genomics Program, Sidra Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

0.044

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.47

M_CAP

Benign

0.012

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.88

PROVEAN

Benign

-0.63

REVEL

Benign

0.083

Sift

Benign

0.039

Sift4G

Benign

0.087

Polyphen

0.22

Vest4

0.68

MVP

0.62

ClinPred

0.015

GERP RS

5.9

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