NM_001267550.2:c.70696G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001267550.2(TTN):​c.70696G>C​(p.Gly23566Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,613,574 control chromosomes in the GnomAD database, including 207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G23566G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.012 ( 23 hom., cov: 32)
Exomes 𝑓: 0.013 ( 184 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

7
4
5

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:28

Conservation

PhyloP100: 7.86

Publications

13 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: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.007964224).
BP6
Variant 2-178575436-C-G is Benign according to our data. Variant chr2-178575436-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178575436-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178575436-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178575436-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178575436-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178575436-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178575436-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178575436-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178575436-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178575436-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178575436-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178575436-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178575436-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178575436-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178575436-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178575436-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178575436-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178575436-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178575436-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178575436-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0116 (1760/152216) while in subpopulation NFE AF = 0.0142 (965/67990). AF 95% confidence interval is 0.0135. There are 23 homozygotes in GnomAd4. There are 945 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 23 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.70696G>C p.Gly23566Arg missense_variant Exon 326 of 363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.70696G>C p.Gly23566Arg missense_variant Exon 326 of 363 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.0116
AC:
1761
AN:
152098
Hom.:
23
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00244
Gnomad AMI
AF:
0.00768
Gnomad AMR
AF:
0.00550
Gnomad ASJ
AF:
0.0112
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00207
Gnomad FIN
AF:
0.0511
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0142
Gnomad OTH
AF:
0.00623
GnomAD2 exomes
AF:
0.0117
AC:
2892
AN:
248240
AF XY:
0.0114
show subpopulations
Gnomad AFR exome
AF:
0.00194
Gnomad AMR exome
AF:
0.00296
Gnomad ASJ exome
AF:
0.0123
Gnomad EAS exome
AF:
0.0000559
Gnomad FIN exome
AF:
0.0523
Gnomad NFE exome
AF:
0.0124
Gnomad OTH exome
AF:
0.00981
GnomAD4 exome
AF:
0.0133
AC:
19395
AN:
1461358
Hom.:
184
Cov.:
36
AF XY:
0.0130
AC XY:
9434
AN XY:
726950
show subpopulations
African (AFR)
AF:
0.00179
AC:
60
AN:
33464
American (AMR)
AF:
0.00295
AC:
132
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.0109
AC:
284
AN:
26118
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39656
South Asian (SAS)
AF:
0.00214
AC:
185
AN:
86248
European-Finnish (FIN)
AF:
0.0478
AC:
2551
AN:
53394
Middle Eastern (MID)
AF:
0.000347
AC:
2
AN:
5762
European-Non Finnish (NFE)
AF:
0.0139
AC:
15493
AN:
1111642
Other (OTH)
AF:
0.0114
AC:
687
AN:
60352
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
1277
2554
3830
5107
6384
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
588
1176
1764
2352
2940
<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:
0.0116
AC:
1760
AN:
152216
Hom.:
23
Cov.:
32
AF XY:
0.0127
AC XY:
945
AN XY:
74400
show subpopulations
African (AFR)
AF:
0.00243
AC:
101
AN:
41560
American (AMR)
AF:
0.00550
AC:
84
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.0112
AC:
39
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5164
South Asian (SAS)
AF:
0.00186
AC:
9
AN:
4830
European-Finnish (FIN)
AF:
0.0511
AC:
542
AN:
10606
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0142
AC:
965
AN:
67990
Other (OTH)
AF:
0.00616
AC:
13
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.497
Heterozygous variant carriers
0
94
189
283
378
472
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
24
48
72
96
120
<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:
0.0120
Hom.:
16
Bravo
AF:
0.00760
TwinsUK
AF:
0.0121
AC:
45
ALSPAC
AF:
0.0125
AC:
48
ESP6500AA
AF:
0.00171
AC:
7
ESP6500EA
AF:
0.0161
AC:
135
ExAC
AF:
0.0106
AC:
1284
Asia WGS
AF:
0.00144
AC:
5
AN:
3478
EpiCase
AF:
0.0109
EpiControl
AF:
0.0104

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:28
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:11
Dec 18, 2023
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 03, 2014
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. -

-
Genetic Services Laboratory, University of Chicago
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

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

- -

Apr 04, 2017
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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

- -

Jun 11, 2012
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Gly20998Arg in Exon 275 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 1.5% (102/6822) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs55801134). -

Aug 16, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely benign
Review Status:criteria provided, single submitter
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

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Apr 09, 2025
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:4
Mar 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

TTN: BS1, BS2 -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

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

- -

Oct 21, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
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 12, 2018
Illumina Laboratory Services, Illumina
Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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 12, 2018
Illumina Laboratory Services, Illumina
Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

- -

Jan 12, 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 12, 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. -

TTN-related disorder Benign:1
Jun 13, 2019
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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 12, 2018
Illumina Laboratory Services, Illumina
Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiomyopathy Benign:1
Nov 30, 2022
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Cardiovascular phenotype Benign:1
Jan 16, 2013
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
Pathogenic
0.88
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.11
CADD
Benign
22
DANN
Benign
0.95
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D;D;.;D;D;D
MetaRNN
Benign
0.0080
T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.24
T
MutationAssessor
Pathogenic
3.1
.;.;.;M;.;.;M
PhyloP100
7.9
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-5.6
D;D;.;.;D;D;.
REVEL
Uncertain
0.64
Sift
Uncertain
0.0040
D;D;.;.;D;D;.
Polyphen
1.0
.;.;.;D;.;.;D
Vest4
0.40
MPC
0.51
ClinPred
0.047
T
GERP RS
5.6
Mutation Taster
=93/7
polymorphism (auto)

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: rs55801134; hg19: chr2-179440163; COSMIC: COSV99045481; COSMIC: COSV99045481; API