2-178751160-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_133379.5(TTN):c.11240A>G(p.Asp3747Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.887 in 1,611,982 control chromosomes in the GnomAD database, including 641,992 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.80 ( 50605 hom., cov: 32)

Exomes 𝑓: 0.90 ( 591387 hom. )

Consequence

TTN
NM_133379.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.57

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=8.624961E-7).

BP6

Variant 2-178751160-T-C is Benign according to our data. Variant chr2-178751160-T-C is described in ClinVar as [Benign]. Clinvar id is 47736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751160-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.923 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_133379.5 link	c.11240A>G	p.Asp3747Gly	missense_variant	Exon 46 of 46	ENST00000360870.10	NP_596870.2	Q8WZ42-6Q7Z3B7
TTN	NM_001267550.2 link	c.11311+1964A>G		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.11240A>G	p.Asp3747Gly	missense_variant	Exon 46 of 46	5	NM_133379.5	ENSP00000354117.4		Q8WZ42-6
TTN	ENST00000589042.5 link	c.11311+1964A>G		intron_variant	Intron 47 of 362	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.804

AC:

121978

AN:

151706

Hom.:

50610

Cov.:

show subpopulations

Gnomad AFR

AF:

0.607

Gnomad AMI

AF:

0.952

Gnomad AMR

AF:

0.691

Gnomad ASJ

AF:

0.897

Gnomad EAS

AF:

0.781

Gnomad SAS

AF:

0.789

Gnomad FIN

AF:

0.892

Gnomad MID

AF:

0.924

Gnomad NFE

AF:

0.929

Gnomad OTH

AF:

0.840

GnomAD3 exomes

AF:

0.820

AC:

203968

AN:

248730

Hom.:

86342

AF XY:

0.836

AC XY:

112454

AN XY:

134514

show subpopulations

Gnomad AFR exome

AF:

0.599

Gnomad AMR exome

AF:

0.558

Gnomad ASJ exome

AF:

0.891

Gnomad EAS exome

AF:

0.756

Gnomad SAS exome

AF:

0.788

Gnomad FIN exome

AF:

0.892

Gnomad NFE exome

AF:

0.929

Gnomad OTH exome

AF:

0.858

GnomAD4 exome

AF:

0.895

AC:

1307511

AN:

1460158

Hom.:

591387

Cov.:

AF XY:

0.895

AC XY:

650284

AN XY:

726312

show subpopulations

Gnomad4 AFR exome

AF:

0.592

Gnomad4 AMR exome

AF:

0.570

Gnomad4 ASJ exome

AF:

0.893

Gnomad4 EAS exome

AF:

0.783

Gnomad4 SAS exome

AF:

0.796

Gnomad4 FIN exome

AF:

0.889

Gnomad4 NFE exome

AF:

0.931

Gnomad4 OTH exome

AF:

0.878

GnomAD4 genome

AF:

0.804

AC:

121992

AN:

151824

Hom.:

50605

Cov.:

AF XY:

0.799

AC XY:

59277

AN XY:

74196

show subpopulations

Gnomad4 AFR

AF:

0.606

Gnomad4 AMR

AF:

0.690

Gnomad4 ASJ

AF:

0.897

Gnomad4 EAS

AF:

0.780

Gnomad4 SAS

AF:

0.790

Gnomad4 FIN

AF:

0.892

Gnomad4 NFE

AF:

0.929

Gnomad4 OTH

AF:

0.842

Alfa

AF:

0.906

Hom.:

110935

Bravo

AF:

0.776

TwinsUK

AF:

0.931

AC:

3452

ALSPAC

AF:

0.928

AC:

3577

ESP6500AA

AF:

0.599

AC:

2636

ESP6500EA

AF:

0.930

AC:

7989

ExAC

AF:

0.826

AC:

100271

Asia WGS

AF:

0.782

AC:

2721

AN:

3478

EpiCase

AF:

0.934

EpiControl

AF:

0.930

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 16, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2014

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.42

MetaRNN

Benign

8.6e-7

MetaSVM

Benign

-0.94

PROVEAN

Benign

-1.4

REVEL

Benign

0.11

Sift

Benign

0.20

Sift4G

Benign

0.32

Polyphen

0.0

Vest4

0.20

ClinPred

0.0091

GERP RS

4.5

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