2-178747124-C-T

Position:

chr2-178747124-C-T

Variant summary

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

The NM_133379.5(TTN):c.15276G>A(p.Leu5092=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00483 in 1,555,344 control chromosomes in the GnomAD database, including 457 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. L5092L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.038 ( 293 hom., cov: 31)

Exomes 𝑓: 0.0021 ( 164 hom. )

Consequence

TTN
NM_133379.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.40

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=-0.91).

BP6

Variant 2-178747124-C-T is Benign according to our data. Variant chr2-178747124-C-T is described in ClinVar as [Benign]. Clinvar id is 47782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178747124-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.4 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_133379.5 linkuse as main transcript	c.15276G>A	p.Leu5092=	synonymous_variant	46/46	ENST00000360870.10	NP_596870.2
TTN	NM_001267550.2 linkuse as main transcript	c.11312-5203G>A		intron_variant		ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000360870.10 linkuse as main transcript	c.15276G>A	p.Leu5092=	synonymous_variant	46/46	5	NM_133379.5	ENSP00000354117		Q8WZ42-6
TTN	ENST00000589042.5 linkuse as main transcript	c.11312-5203G>A		intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.1223+4154C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0383

AC:

4523

AN:

118132

Hom.:

294

Cov.:

show subpopulations

Gnomad AFR

AF:

0.137

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000502

Gnomad SAS

AF:

0.000821

Gnomad FIN

AF:

0.000139

Gnomad MID

AF:

0.0217

Gnomad NFE

AF:

0.000726

Gnomad OTH

AF:

0.0368

GnomAD3 exomes

AF:

0.00530

AC:

1294

AN:

244026

Hom.:

AF XY:

0.00401

AC XY:

531

AN XY:

132288

show subpopulations

Gnomad AFR exome

AF:

0.0750

Gnomad AMR exome

AF:

0.00280

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000134

Gnomad FIN exome

AF:

0.0000471

Gnomad NFE exome

AF:

0.000289

Gnomad OTH exome

AF:

0.00306

GnomAD4 exome

AF:

0.00206

AC:

2964

AN:

1437104

Hom.:

164

Cov.:

AF XY:

0.00176

AC XY:

1258

AN XY:

715440

show subpopulations

Gnomad4 AFR exome

AF:

0.0775

Gnomad4 AMR exome

AF:

0.00339

Gnomad4 ASJ exome

AF:

0.0000781

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000222

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.000114

Gnomad4 OTH exome

AF:

0.00591

GnomAD4 genome

AF:

0.0384

AC:

4545

AN:

118240

Hom.:

293

Cov.:

AF XY:

0.0366

AC XY:

2087

AN XY:

57018

show subpopulations

Gnomad4 AFR

AF:

0.138

Gnomad4 AMR

AF:

0.0115

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000503

Gnomad4 SAS

AF:

0.00110

Gnomad4 FIN

AF:

0.000139

Gnomad4 NFE

AF:

0.000726

Gnomad4 OTH

AF:

0.0365

Alfa

AF:

0.0246

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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	Apr 11, 2012	Leu5092Leu in exon 45A of TTN: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and has been identifie d in 8.4% (315/3736) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs72 648910). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 12, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.23

DANN

Benign

0.57

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