chr2-178725602-C-T

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.20602G>A​(p.Gly6868Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0158 in 1,608,306 control chromosomes in the GnomAD database, including 239 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 21 hom., cov: 33)
Exomes 𝑓: 0.016 ( 218 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

4
4
7

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26

Conservation

PhyloP100: 5.85

Publications

14 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=0.007750064).
BP6
Variant 2-178725602-C-T is Benign according to our data. Variant chr2-178725602-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 46672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178725602-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 46672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178725602-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 46672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178725602-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 46672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178725602-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 46672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178725602-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 46672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178725602-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 46672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178725602-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 46672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178725602-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 46672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178725602-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 46672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178725602-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 46672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178725602-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 46672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178725602-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 46672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178725602-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 46672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178725602-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 46672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178725602-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 46672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178725602-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 46672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178725602-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 46672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178725602-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 46672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178725602-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 46672.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 (1767/152168) while in subpopulation NFE AF = 0.0177 (1204/67990). AF 95% confidence interval is 0.0169. There are 21 homozygotes in GnomAd4. There are 805 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 21 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.20602G>A p.Gly6868Arg missense_variant Exon 71 of 363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.20602G>A p.Gly6868Arg missense_variant Exon 71 of 363 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.0116
AC:
1769
AN:
152050
Hom.:
21
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00326
Gnomad AMI
AF:
0.0396
Gnomad AMR
AF:
0.0109
Gnomad ASJ
AF:
0.0115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00810
Gnomad FIN
AF:
0.0105
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0177
Gnomad OTH
AF:
0.0172
GnomAD2 exomes
AF:
0.0118
AC:
2870
AN:
243616
AF XY:
0.0121
show subpopulations
Gnomad AFR exome
AF:
0.00273
Gnomad AMR exome
AF:
0.00522
Gnomad ASJ exome
AF:
0.00890
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0129
Gnomad NFE exome
AF:
0.0179
Gnomad OTH exome
AF:
0.0158
GnomAD4 exome
AF:
0.0162
AC:
23591
AN:
1456138
Hom.:
218
Cov.:
31
AF XY:
0.0160
AC XY:
11547
AN XY:
723872
show subpopulations
African (AFR)
AF:
0.00256
AC:
85
AN:
33262
American (AMR)
AF:
0.00668
AC:
296
AN:
44292
Ashkenazi Jewish (ASJ)
AF:
0.00943
AC:
243
AN:
25764
East Asian (EAS)
AF:
0.0000505
AC:
2
AN:
39608
South Asian (SAS)
AF:
0.00787
AC:
670
AN:
85118
European-Finnish (FIN)
AF:
0.0133
AC:
705
AN:
53172
Middle Eastern (MID)
AF:
0.0124
AC:
71
AN:
5726
European-Non Finnish (NFE)
AF:
0.0185
AC:
20571
AN:
1109102
Other (OTH)
AF:
0.0158
AC:
948
AN:
60094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.484
Heterozygous variant carriers
0
1353
2705
4058
5410
6763
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
776
1552
2328
3104
3880
<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:
1767
AN:
152168
Hom.:
21
Cov.:
33
AF XY:
0.0108
AC XY:
805
AN XY:
74392
show subpopulations
African (AFR)
AF:
0.00325
AC:
135
AN:
41552
American (AMR)
AF:
0.0109
AC:
167
AN:
15272
Ashkenazi Jewish (ASJ)
AF:
0.0115
AC:
40
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5168
South Asian (SAS)
AF:
0.00790
AC:
38
AN:
4810
European-Finnish (FIN)
AF:
0.0105
AC:
111
AN:
10594
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0177
AC:
1204
AN:
67990
Other (OTH)
AF:
0.0171
AC:
36
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
88
176
263
351
439
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
20
40
60
80
100
<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:
0.0154
Hom.:
71
Bravo
AF:
0.0118
TwinsUK
AF:
0.0210
AC:
78
ALSPAC
AF:
0.0228
AC:
88
ESP6500AA
AF:
0.00349
AC:
13
ESP6500EA
AF:
0.0173
AC:
142
ExAC
AF:
0.0112
AC:
1355
Asia WGS
AF:
0.00462
AC:
16
AN:
3476

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:26
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:10
Apr 06, 2017
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 03, 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. -

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

- -

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

- -

-
PreventionGenetics, part of Exact Sciences
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

- -

Apr 18, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely benign
Review Status:criteria provided, single submitter
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

- -

Mar 22, 2012
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Gly5624Arg in exon 68 of TTN: This variant is not expected to have clinical sign ificance because it has been identified in 1.7% (112/6604) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs17355460). -

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

- -

not provided Benign:5
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

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

- -

Nov 29, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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

- -

Jun 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

TTN: BS1, BS2 -

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: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 13, 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
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. -

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

- -

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: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. -

Cardiovascular phenotype Benign:1
Jan 08, 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
Uncertain
0.41
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.22
CADD
Uncertain
24
DANN
Benign
0.85
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.85
T;D;.;T
MetaRNN
Benign
0.0078
T;T;T;T
MetaSVM
Uncertain
0.56
D
PhyloP100
5.9
PrimateAI
Uncertain
0.64
T
PROVEAN
Pathogenic
-4.6
D;.;.;.
REVEL
Uncertain
0.60
Sift
Benign
0.085
T;.;.;.
Polyphen
1.0
.;.;D;D
Vest4
0.18
MutPred
0.78
.;.;Loss of catalytic residue at A6550 (P = 0.0402);Loss of catalytic residue at A6550 (P = 0.0402);
MPC
0.50
ClinPred
0.038
T
GERP RS
5.9
Mutation Taster
=29/71
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs17355460; hg19: chr2-179590329; COSMIC: COSV60066329; API