chr2-178740686-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.12547A>G(p.Lys4183Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,613,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K4183N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 2.20

Publications

1 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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.047561526).

BP6

Variant 2-178740686-T-C is Benign according to our data. Variant chr2-178740686-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229594. Variant chr2-178740686-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229594. Variant chr2-178740686-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229594. Variant chr2-178740686-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229594. Variant chr2-178740686-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229594. Variant chr2-178740686-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229594. Variant chr2-178740686-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229594. Variant chr2-178740686-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229594. Variant chr2-178740686-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229594. Variant chr2-178740686-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229594. Variant chr2-178740686-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229594. Variant chr2-178740686-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229594. Variant chr2-178740686-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229594. Variant chr2-178740686-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229594. Variant chr2-178740686-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229594. Variant chr2-178740686-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229594. Variant chr2-178740686-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229594. Variant chr2-178740686-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229594. Variant chr2-178740686-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229594. Variant chr2-178740686-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229594.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.12547A>G	p.Lys4183Glu	missense_variant	Exon 48 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.12547A>G	p.Lys4183Glu	missense_variant	Exon 48 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152176

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:

0.000235

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000105

AC:

AN:

248470

AF XY:

0.0000891

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:

0.000205

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000759

AC:

111

AN:

1461590

Hom.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

727088

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000917

AC:

102

AN:

1111798

Other (OTH)

AF:

0.0000994

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

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:

0.000105

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.000132

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.000149

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2Benign:1

Apr 04, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Lys3945Glu va riant in TTN has not been previously reported in individuals with cardiomyopathy , but has been identified in 16/66676 European chromosomes by the Exome Aggregat ion Consortium (http://exac.broadinstitute.org; dbSNP rs201565932). Computationa l prediction tools and conservation analyses do not provide strong support for o r against an impact to the protein. In summary, while the clinical significance of the p.Lys3945Glu variant is uncertain, these data suggest that it is more lik ely to be benign. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2025

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.10361-2326A>G is located at a position not widely known to affect splicing. This variant corresponds to c.12547A>G, p.Lys4183Glu in NM_001267550. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0001 in 248470 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.0001 vs 0.00039), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.10361-2326A>G 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: 229594). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1Benign:1

Feb 22, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TTN: PM2, BP4 -

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

Uncertain:1

Dec 28, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Aug 22, 2019

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

0.087

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.61

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.75

T;T;.;T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.048

T;T;T;T;T;T

MetaSVM

Benign

-0.96

PhyloP100

2.2

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.78

N;.;.;N;N;.

REVEL

Benign

0.12

Sift

Benign

0.095

T;.;.;T;T;.

Vest4

0.090

MVP

0.24

MPC

0.12

ClinPred

0.036

GERP RS

3.0

Mutation Taster

=86/14

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