rs751902051

Variant summary

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

The NM_001267550.2(TTN):​c.19728C>T​(p.Phe6576Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.0000535 in 1,588,452 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: 0.000056 ( 0 hom. )

Consequence

TTN
NM_001267550.2 synonymous

Scores

2

Clinical Significance

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

Conservation

PhyloP100: 5.41

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-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 (BayesDel_noAF=-0.42).
BP6
Variant 2-178727850-G-A is Benign according to our data. Variant chr2-178727850-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228063. Variant chr2-178727850-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228063. Variant chr2-178727850-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228063. Variant chr2-178727850-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228063. Variant chr2-178727850-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228063. Variant chr2-178727850-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228063. Variant chr2-178727850-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228063. Variant chr2-178727850-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228063. Variant chr2-178727850-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228063. Variant chr2-178727850-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228063. Variant chr2-178727850-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228063. Variant chr2-178727850-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228063. Variant chr2-178727850-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228063. Variant chr2-178727850-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228063. Variant chr2-178727850-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228063. Variant chr2-178727850-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228063. Variant chr2-178727850-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228063. Variant chr2-178727850-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228063. Variant chr2-178727850-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228063. Variant chr2-178727850-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228063.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.19728C>T p.Phe6576Phe synonymous_variant Exon 68 of 363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.19728C>T p.Phe6576Phe synonymous_variant Exon 68 of 363 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152086
Hom.:
0
Cov.:
33
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:
0.0000351
AC:
8
AN:
227806
AF XY:
0.0000243
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:
0.0000757
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000557
AC:
80
AN:
1436366
Hom.:
0
Cov.:
31
AF XY:
0.0000548
AC XY:
39
AN XY:
712134
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32308
American (AMR)
AF:
0.0000490
AC:
2
AN:
40812
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24952
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39376
South Asian (SAS)
AF:
0.00
AC:
0
AN:
80790
European-Finnish (FIN)
AF:
0.0000190
AC:
1
AN:
52698
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5606
European-Non Finnish (NFE)
AF:
0.0000681
AC:
75
AN:
1100624
Other (OTH)
AF:
0.0000338
AC:
2
AN:
59200
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.465
Heterozygous variant carriers
0
5
10
15
20
25
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:
0.0000329
AC:
5
AN:
152086
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74274
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41422
American (AMR)
AF:
0.00
AC:
0
AN:
15260
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4820
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10612
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000735
AC:
5
AN:
68000
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.445
Heterozygous variant carriers
0
1
1
2
2
3
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:
0.0000624
Hom.:
0
Bravo
AF:
0.0000340

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Sep 18, 2020
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Aug 17, 2015
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:1
Jun 25, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

p.Phe5332Phe in exon 65 of TTN: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 5/64462 European c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org). -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Nov 24, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.42
CADD
Benign
6.4
DANN
Benign
0.69
PhyloP100
5.4
Mutation Taster
=56/44
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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: rs751902051; hg19: chr2-179592577; API