2-178546263-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BP6

The NM_001267550.2(TTN):c.95068G>A(p.Val31690Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,613,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 7.91

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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.35097033).

BP6

Variant 2-178546263-C-T is Benign according to our data. Variant chr2-178546263-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165714. Variant chr2-178546263-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165714. Variant chr2-178546263-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165714. Variant chr2-178546263-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165714. Variant chr2-178546263-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165714. Variant chr2-178546263-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165714. Variant chr2-178546263-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165714. Variant chr2-178546263-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165714. Variant chr2-178546263-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165714. Variant chr2-178546263-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165714. Variant chr2-178546263-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165714. Variant chr2-178546263-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165714. Variant chr2-178546263-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165714. Variant chr2-178546263-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165714. Variant chr2-178546263-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165714. Variant chr2-178546263-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165714. Variant chr2-178546263-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165714. Variant chr2-178546263-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165714. Variant chr2-178546263-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165714. Variant chr2-178546263-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165714.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.95068G>A	p.Val31690Met	missense_variant	Exon 342 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.95068G>A	p.Val31690Met	missense_variant	Exon 342 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000805

AC:

AN:

248580

AF XY:

0.00000742

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:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000479

AC:

AN:

1461360

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

726950

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000603

AC:

AN:

1111612

Other (OTH)

AF:

0.0000331

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.0000328

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Apr 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TTN c.87364G>A (p.Val29122Met) results in a conservative amino acid change located in the A-band region of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 248580 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.87364G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 165714). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Feb 06, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Val29122Met variant in TTN has not been reported in individuals with cardiom yopathy or in large population studies. Computational analyses (biochemical amin o acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Additional information i s needed to fully assess the clinical significance of the Val29122Met variant. -

Cardiovascular phenotype

Uncertain:1

Apr 27, 2018

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.V22625M variant (also known as c.67873G>A), located in coding exon 169 of the TTN gene, results from a G to A substitution at nucleotide position 67873. The valine at codon 22625 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Jun 01, 2018

GeneDx

Significance:Likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Uncertain

0.028

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Pathogenic

0.68

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;.;D;D;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.35

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

MetaSVM

Uncertain

-0.0082

MutationAssessor

Uncertain

2.2

.;.;.;M;.;.;M

PhyloP100

7.9

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.9

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

REVEL

Uncertain

0.52

Sift

Uncertain

0.0070

D;D;.;.;D;D;.

Polyphen

0.98

.;.;.;D;.;.;D

Vest4

0.34

MutPred

0.72

.;.;.;Gain of disorder (P = 0.0775);.;.;Gain of disorder (P = 0.0775);

MVP

0.65

MPC

0.37

ClinPred

0.46

GERP RS

4.8

Mutation Taster

=95/5

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over