chr2-178740978-A-G

Position:

chr2-178740978-A-G

Variant summary

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

The NM_001267550.2(TTN):c.12255T>C(p.Ile4085=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0527 in 1,613,866 control chromosomes in the GnomAD database, including 3,840 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.050 ( 377 hom., cov: 32)

Exomes 𝑓: 0.053 ( 3463 hom. )

Consequence

TTN
NM_001267550.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.0280

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 2-178740978-A-G is Benign according to our data. Variant chr2-178740978-A-G is described in ClinVar as [Benign]. Clinvar id is 47824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178740978-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.028 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.178 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.12255T>C	p.Ile4085=	synonymous_variant	48/363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.12255T>C	p.Ile4085=	synonymous_variant	48/363	5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.1134-1903A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0500

AC:

7607

AN:

152150

Hom.:

376

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0117

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.137

Gnomad ASJ

AF:

0.0487

Gnomad EAS

AF:

0.188

Gnomad SAS

AF:

0.0236

Gnomad FIN

AF:

0.0512

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0453

Gnomad OTH

AF:

0.0463

GnomAD3 exomes

AF:

0.0798

AC:

19813

AN:

248302

Hom.:

1719

AF XY:

0.0703

AC XY:

9463

AN XY:

134666

show subpopulations

Gnomad AFR exome

AF:

0.0109

Gnomad AMR exome

AF:

0.241

Gnomad ASJ exome

AF:

0.0484

Gnomad EAS exome

AF:

0.208

Gnomad SAS exome

AF:

0.0190

Gnomad FIN exome

AF:

0.0524

Gnomad NFE exome

AF:

0.0445

Gnomad OTH exome

AF:

0.0675

GnomAD4 exome

AF:

0.0530

AC:

77449

AN:

1461598

Hom.:

3463

Cov.:

AF XY:

0.0512

AC XY:

37232

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.00932

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:

0.0452

Gnomad4 OTH exome

AF:

0.0517

GnomAD4 genome

AF:

0.0500

AC:

7610

AN:

152268

Hom.:

377

Cov.:

AF XY:

0.0515

AC XY:

3834

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0116

Gnomad4 AMR

AF:

0.138

Gnomad4 ASJ

AF:

0.0487

Gnomad4 EAS

AF:

0.188

Gnomad4 SAS

AF:

0.0230

Gnomad4 FIN

AF:

0.0512

Gnomad4 NFE

AF:

0.0454

Gnomad4 OTH

AF:

0.0449

Alfa

AF:

0.0489

Hom.:

363

Bravo

AF:

0.0609

Asia WGS

AF:

0.0770

AC:

266

AN:

3478

EpiCase

AF:

0.0407

EpiControl

AF:

0.0431

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 20, 2012	- -

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

- -

Early-onset myopathy with fatal cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Tibial muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Myopathy, myofibrillar, 9, with early respiratory failure

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

Apr 20, 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

-0.62

CADD

Benign

0.21

DANN

Benign

0.75

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