chr2-178718084-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001267550.2(TTN):c.24922C>T(p.Pro8308Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.41

Publications

0 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 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 was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13394871).

BP6

Variant 2-178718084-G-A is Benign according to our data. Variant chr2-178718084-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 504545. Variant chr2-178718084-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 504545. Variant chr2-178718084-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 504545. Variant chr2-178718084-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 504545. Variant chr2-178718084-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 504545. Variant chr2-178718084-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 504545. Variant chr2-178718084-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 504545. Variant chr2-178718084-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 504545. Variant chr2-178718084-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 504545. Variant chr2-178718084-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 504545. Variant chr2-178718084-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 504545. Variant chr2-178718084-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 504545. Variant chr2-178718084-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 504545. Variant chr2-178718084-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 504545. Variant chr2-178718084-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 504545. Variant chr2-178718084-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 504545. Variant chr2-178718084-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 504545. Variant chr2-178718084-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 504545. Variant chr2-178718084-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 504545. Variant chr2-178718084-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 504545.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.24922C>T	p.Pro8308Ser	missense_variant	Exon 86 of 363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.24922C>T	p.Pro8308Ser	missense_variant	Exon 86 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

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:

0.00

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.0000281

AC:

AN:

248672

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.000452

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461284

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726930

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53206

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111708

Other (OTH)

AF:

0.0000166

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.000138

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.000483

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67996

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.000285

Hom.:

Bravo

AF:

0.000200

ESP6500AA

AF:

0.000790

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Pro7064Ser variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 4/9800 African chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs37 3770383). Computational prediction tools and conservation analysis do not provid e strong support for or against an impact to the protein. In summary, the clinic al significance of the p.Pro7064Ser variant is uncertain. -

not provided

Uncertain:1

Jun 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The TTN c.24922C>T; p.Pro8308Ser variant (rs373770383; ClinVar Variation ID: 504545) is rare in the general population (<0.2% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Pro8308Ser variant cannot be determined with certainty. References: Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). PMID: 26567375. Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. PMID: 22335739. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. PMID: 24625729. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.90

Eigen

Benign

0.11

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.69

T;T;.;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-0.85

PhyloP100

2.4

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.4

D;.;.;.

REVEL

Benign

0.18

Sift

Benign

0.50

T;.;.;.

Polyphen

0.12

.;.;B;B

Vest4

0.33

MVP

0.19

MPC

0.097

ClinPred

0.061

GERP RS

6.2

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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