2-178670230-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_001267550.2(TTN):c.35374C>T(p.Pro11792Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P11792L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.78

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:

LOC124906100 (HGNC:):

LOC124906100 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21546727).

BP6

Variant 2-178670230-G-A is Benign according to our data. Variant chr2-178670230-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 179766.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.35374C>T	p.Pro11792Ser	missense_variant	Exon 157 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.35374C>T	p.Pro11792Ser	missense_variant	Exon 157 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1324688

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

654004

African (AFR)

AF:

0.00

AC:

AN:

27080

American (AMR)

AF:

0.00

AC:

AN:

25580

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21964

East Asian (EAS)

AF:

0.00

AC:

AN:

34000

South Asian (SAS)

AF:

0.00

AC:

AN:

56926

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49220

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1050444

Other (OTH)

AF:

0.00

AC:

AN:

54180

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jun 18, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pro10491Ser in exon 152 of TTN: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, 4 mammals (guinea pig, chinchilla, dolphin, and killer whale) have a serine (Ser) at this position despite high nearby amino acid conservation. In addition , computational prediction tools do not suggest a high likelihood of impact to t he protein. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.94

Eigen

Benign

-0.068

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.40

T;T;.;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.22

T;T;T;T

MetaSVM

Benign

-0.88

PhyloP100

1.8

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.6

D;.;.;.

REVEL

Benign

0.12

Sift

Benign

0.068

T;.;.;.

Polyphen

0.0

.;.;B;B

Vest4

0.25

MutPred

0.28

.;.;Loss of catalytic residue at P11418 (P = 0.0016);Loss of catalytic residue at P11418 (P = 0.0016);

MVP

0.20

MPC

0.084

ClinPred

0.18

GERP RS

2.1

Mutation Taster

=88/12

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over