rs1552280

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001267550.2(TTN):​c.3884C>T​(p.Ser1295Leu) variant causes a missense change. The variant allele was found at a frequency of 0.978 in 1,613,600 control chromosomes in the GnomAD database, including 772,469 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.95 ( 68587 hom., cov: 32)
Exomes 𝑓: 0.98 ( 703882 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

16

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:25

Conservation

PhyloP100: 6.29
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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=6.196605E-7).
BP6
Variant 2-178779308-G-A is Benign according to our data. Variant chr2-178779308-G-A is described in ClinVar as [Benign]. Clinvar id is 47001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178779308-G-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.3884C>T p.Ser1295Leu missense_variant Exon 23 of 363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7
TTNNM_133379.5 linkc.3884C>T p.Ser1295Leu missense_variant Exon 23 of 46 ENST00000360870.10 NP_596870.2 Q8WZ42-6Q7Z3B7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.3884C>T p.Ser1295Leu missense_variant Exon 23 of 363 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7
TTNENST00000360870.10 linkc.3884C>T p.Ser1295Leu missense_variant Exon 23 of 46 5 NM_133379.5 ENSP00000354117.4 Q8WZ42-6

Frequencies

GnomAD3 genomes
AF:
0.948
AC:
144176
AN:
152132
Hom.:
68561
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.869
Gnomad AMI
AF:
0.843
Gnomad AMR
AF:
0.964
Gnomad ASJ
AF:
0.994
Gnomad EAS
AF:
0.872
Gnomad SAS
AF:
0.951
Gnomad FIN
AF:
0.980
Gnomad MID
AF:
0.978
Gnomad NFE
AF:
0.991
Gnomad OTH
AF:
0.948
GnomAD3 exomes
AF:
0.962
AC:
240635
AN:
250190
Hom.:
115921
AF XY:
0.965
AC XY:
130580
AN XY:
135248
show subpopulations
Gnomad AFR exome
AF:
0.869
Gnomad AMR exome
AF:
0.939
Gnomad ASJ exome
AF:
0.992
Gnomad EAS exome
AF:
0.881
Gnomad SAS exome
AF:
0.958
Gnomad FIN exome
AF:
0.978
Gnomad NFE exome
AF:
0.990
Gnomad OTH exome
AF:
0.970
GnomAD4 exome
AF:
0.981
AC:
1433607
AN:
1461350
Hom.:
703882
Cov.:
54
AF XY:
0.981
AC XY:
713137
AN XY:
726998
show subpopulations
Gnomad4 AFR exome
AF:
0.866
Gnomad4 AMR exome
AF:
0.943
Gnomad4 ASJ exome
AF:
0.993
Gnomad4 EAS exome
AF:
0.870
Gnomad4 SAS exome
AF:
0.958
Gnomad4 FIN exome
AF:
0.977
Gnomad4 NFE exome
AF:
0.992
Gnomad4 OTH exome
AF:
0.971
GnomAD4 genome
AF:
0.947
AC:
144254
AN:
152250
Hom.:
68587
Cov.:
32
AF XY:
0.948
AC XY:
70544
AN XY:
74432
show subpopulations
Gnomad4 AFR
AF:
0.868
Gnomad4 AMR
AF:
0.964
Gnomad4 ASJ
AF:
0.994
Gnomad4 EAS
AF:
0.872
Gnomad4 SAS
AF:
0.951
Gnomad4 FIN
AF:
0.980
Gnomad4 NFE
AF:
0.991
Gnomad4 OTH
AF:
0.948
Alfa
AF:
0.980
Hom.:
120312
Bravo
AF:
0.940
TwinsUK
AF:
0.992
AC:
3680
ALSPAC
AF:
0.992
AC:
3825
ESP6500AA
AF:
0.872
AC:
3841
ESP6500EA
AF:
0.991
AC:
8524
ExAC
AF:
0.960
AC:
116549
Asia WGS
AF:
0.907
AC:
3156
AN:
3478
EpiCase
AF:
0.991
EpiControl
AF:
0.991

ClinVar

Significance: Benign
Submissions summary: Benign:25
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:12
-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 16, 2011
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 24, 2013
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: research

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 09, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 31, 2013
GeneDx
Significance: 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. -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 15, 2015
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 15, 2013
Genetic Services Laboratory, University of Chicago
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:2
Sep 10, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Early-onset myopathy with fatal cardiomyopathy Benign:2
Sep 10, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Jan 15, 2019
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Tibial muscular dystrophy Benign:2
Sep 10, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Myopathy, myofibrillar, 9, with early respiratory failure Benign:2
Sep 10, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dilated cardiomyopathy 1G Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype Benign:1
Jul 11, 2012
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: 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
0.036
BayesDel_addAF
Benign
-0.57
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
21
DANN
Benign
0.97
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.10
FATHMM_MKL
Benign
0.73
D
LIST_S2
Benign
0.084
T;T;T;.;T;T;T;T
MetaRNN
Benign
6.2e-7
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.96
T
PrimateAI
Benign
0.35
T
PROVEAN
Benign
2.2
N;N;.;.;N;N;.;N
REVEL
Benign
0.18
Sift
Benign
0.33
T;T;.;.;T;T;.;T
Sift4G
Benign
0.75
.;.;.;.;.;.;.;T
Polyphen
0.0
.;.;.;B;.;.;B;B
Vest4
0.038
MPC
0.074
ClinPred
0.017
T
GERP RS
5.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1552280; hg19: chr2-179644035; API