chr2-178789404-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001267550.2(TTN):c.2032A>G(p.Thr678Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,613,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T678T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.01

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
dilated cardiomyopathy 1G
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
early-onset myopathy with fatal cardiomyopathy
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
TTN-related myopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
myopathy, myofibrillar, 9, with early respiratory failure
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics
tibial muscular dystrophy
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
autosomal recessive limb-girdle muscular dystrophy type 2J
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
hypertrophic cardiomyopathy 9
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive centronuclear myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
congenital myopathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hereditary skeletal muscle disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

TTN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0465658).

BP6

Variant 2-178789404-T-C is Benign according to our data. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716. Variant chr2-178789404-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238716.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.2032A>G	p.Thr678Ala	missense_variant	Exon 13 of 363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7
TTN	NM_133379.5 link	c.2032A>G	p.Thr678Ala	missense_variant	Exon 13 of 46	ENST00000360870.10	NP_596870.2	Q8WZ42-6Q7Z3B7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.2032A>G	p.Thr678Ala	missense_variant	Exon 13 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7
TTN	ENST00000360870.10 link	c.2032A>G	p.Thr678Ala	missense_variant	Exon 13 of 46	5	NM_133379.5	ENSP00000354117.4		Q8WZ42-6

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251016

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000541

AC:

AN:

1461314

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

726956

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39638

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000702

AC:

AN:

1111600

Other (OTH)

AF:

0.0000166

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67980

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.583

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G

Uncertain:1

Feb 08, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Nov 11, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Nov 09, 2020

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.84

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.0075

LIST_S2

Benign

0.47

T;T;T;.;T;T;T;T;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.047

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.42

N;N;.;.;N;N;.;N;N

REVEL

Benign

0.061

Sift

Benign

0.99

T;T;.;.;T;T;.;T;T

Sift4G

Benign

0.58

.;.;.;.;.;.;.;T;.

Polyphen

0.0

.;.;.;B;.;.;B;B;.

Vest4

0.036

MutPred

0.34

Gain of phosphorylation at T675 (P = 0.0877);.;Gain of phosphorylation at T675 (P = 0.0877);Gain of phosphorylation at T675 (P = 0.0877);.;.;Gain of phosphorylation at T675 (P = 0.0877);Gain of phosphorylation at T675 (P = 0.0877);.;

MVP

0.055

MPC

0.082

ClinPred

0.037

GERP RS

4.1

Mutation Taster

=81/19

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over