chr2-178530695-A-G

Variant summary

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

The NM_001267550.2(TTN):​c.105920T>C​(p.Val35307Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000521 in 1,613,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V35307V) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.00018 ( 0 hom., cov: 33)
Exomes š‘“: 0.000039 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

2
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.63

Publications

2 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 -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.11884019).
BP6
Variant 2-178530695-A-G is Benign according to our data. Variant chr2-178530695-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 466745.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.105920T>C p.Val35307Ala missense_variant Exon 358 of 363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.105920T>C p.Val35307Ala missense_variant Exon 358 of 363 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.000177
AC:
27
AN:
152118
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00170
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000964
AC:
24
AN:
249034
AF XY:
0.000111
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000609
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.0000390
AC:
57
AN:
1461680
Hom.:
0
Cov.:
33
AF XY:
0.0000399
AC XY:
29
AN XY:
727118
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33478
American (AMR)
AF:
0.000671
AC:
30
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53394
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000216
AC:
24
AN:
1111854
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60374
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.488
Heterozygous variant carriers
0
4
8
13
17
21
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome 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
GnomAD4 genome
AF:
0.000177
AC:
27
AN:
152118
Hom.:
0
Cov.:
33
AF XY:
0.000188
AC XY:
14
AN XY:
74316
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41406
American (AMR)
AF:
0.00170
AC:
26
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10600
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68028
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.484
Heterozygous variant carriers
0
1
3
4
6
7
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:
0.0000847
Hom.:
0
Bravo
AF:
0.000223
ExAC
AF:
0.0000248
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

TTN-related disorder Uncertain:1
Feb 14, 2024
PreventionGenetics, part of Exact Sciences
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

The TTN c.105920T>C variant is predicted to result in the amino acid substitution p.Val35307Ala. This variant was reported in an individual with dilated cardiomyopathy; however, this individual also carried a TTN frameshift variant (described as p.Val32739Ala in transcript NM_133378 in online supplementary file 2, van Lint et al. 2019. PubMed ID: 30847666). This variant is reported in 0.061% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Dec 14, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 35307 of the TTN protein (p.Val35307Ala). This variant is present in population databases (rs780629996, gnomAD 0.07%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 30847666). This variant is also known as p.Val32739Ala. ClinVar contains an entry for this variant (Variation ID: 466745). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant is located in the M band of TTN (PMID: 25589632). Non-truncating variants in this region may be relevant for neuromuscular disorders, but have not been definitively shown to cause cardiomyopathy (PMID: 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Benign:1
May 14, 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
Benign
0.17
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
18
DANN
Benign
0.86
Eigen
Benign
-0.19
Eigen_PC
Benign
-0.091
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.82
T;T;T;.;T;T;T
M_CAP
Benign
0.065
D
MetaRNN
Benign
0.12
T;T;T;T;T;T;T
MetaSVM
Benign
-0.33
T
MutationAssessor
Benign
0.95
.;.;.;L;.;.;L
PhyloP100
3.6
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-2.0
N;N;.;.;N;N;.
REVEL
Uncertain
0.33
Sift
Benign
0.14
T;T;.;.;T;T;.
Polyphen
0.025
.;.;.;B;.;.;B
Vest4
0.14
MutPred
0.69
.;.;.;Loss of catalytic residue at V33666 (P = 0.0479);.;.;Loss of catalytic residue at V33666 (P = 0.0479);
MVP
0.53
MPC
0.11
ClinPred
0.051
T
GERP RS
5.1
Mutation Taster
=71/29
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: rs780629996; hg19: chr2-179395422; API