chr2-178740686-T-C

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: š‘“ 0.00011 ( 0 hom., cov: 32)
Exomes š‘“: 0.000076 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

16

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-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]

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
TTNNM_001267550.2 linkc.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
TTNENST00000589042.5 linkc.12547A>G p.Lys4183Glu missense_variant Exon 48 of 363 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152176
Hom.:
0
Cov.:
32
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:
26
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.:
0
Cov.:
32
AF XY:
0.0000770
AC XY:
56
AN XY:
727088
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33472
American (AMR)
AF:
0.00
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39686
South Asian (SAS)
AF:
0.0000348
AC:
3
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53392
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
0.0000917
AC:
102
AN:
1111798
Other (OTH)
AF:
0.0000994
AC:
6
AN:
60366
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.464
Heterozygous variant carriers
0
7
14
21
28
35
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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:
16
AN:
152176
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74350
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41452
American (AMR)
AF:
0.00
AC:
0
AN:
15272
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5186
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000235
AC:
16
AN:
68026
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.503
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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.:
0
Bravo
AF:
0.0000718
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000122
AC:
1
ExAC
AF:
0.000149
AC:
18
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
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
14
DANN
Benign
0.61
Eigen
Benign
-0.59
Eigen_PC
Benign
-0.49
FATHMM_MKL
Benign
0.67
D
LIST_S2
Benign
0.75
T;T;.;T;T;T
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.048
T;T;T;T;T;T
MetaSVM
Benign
-0.96
T
PhyloP100
2.2
PrimateAI
Benign
0.27
T
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
T
GERP RS
3.0
Mutation Taster
=86/14
polymorphism

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

Other links and lift over

dbSNP: rs201565932; hg19: chr2-179605413; API