chr2-178607966-A-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001267550.2(TTN):​c.52821T>C​(p.Asp17607Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0237 in 1,612,930 control chromosomes in the GnomAD database, including 646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 66 hom., cov: 32)
Exomes 𝑓: 0.024 ( 580 hom. )

Consequence

TTN
NM_001267550.2 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23

Conservation

PhyloP100: 1.13

Publications

7 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]

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.46).
BP6
Variant 2-178607966-A-G is Benign according to our data. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=1.13 with no splicing effect.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0883 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.52821T>C p.Asp17607Asp synonymous_variant Exon 276 of 363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.52821T>C p.Asp17607Asp synonymous_variant Exon 276 of 363 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.0216
AC:
3277
AN:
151918
Hom.:
67
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00466
Gnomad AMI
AF:
0.0307
Gnomad AMR
AF:
0.0234
Gnomad ASJ
AF:
0.0193
Gnomad EAS
AF:
0.0951
Gnomad SAS
AF:
0.00954
Gnomad FIN
AF:
0.0450
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.0231
Gnomad OTH
AF:
0.0220
GnomAD2 exomes
AF:
0.0294
AC:
7313
AN:
248414
AF XY:
0.0278
show subpopulations
Gnomad AFR exome
AF:
0.00504
Gnomad AMR exome
AF:
0.0339
Gnomad ASJ exome
AF:
0.0141
Gnomad EAS exome
AF:
0.103
Gnomad FIN exome
AF:
0.0475
Gnomad NFE exome
AF:
0.0234
Gnomad OTH exome
AF:
0.0279
GnomAD4 exome
AF:
0.0240
AC:
35025
AN:
1460894
Hom.:
580
Cov.:
32
AF XY:
0.0236
AC XY:
17122
AN XY:
726744
show subpopulations
African (AFR)
AF:
0.00416
AC:
139
AN:
33422
American (AMR)
AF:
0.0323
AC:
1443
AN:
44690
Ashkenazi Jewish (ASJ)
AF:
0.0143
AC:
374
AN:
26114
East Asian (EAS)
AF:
0.0923
AC:
3651
AN:
39560
South Asian (SAS)
AF:
0.00933
AC:
805
AN:
86238
European-Finnish (FIN)
AF:
0.0490
AC:
2617
AN:
53396
Middle Eastern (MID)
AF:
0.0116
AC:
67
AN:
5762
European-Non Finnish (NFE)
AF:
0.0220
AC:
24494
AN:
1111388
Other (OTH)
AF:
0.0238
AC:
1435
AN:
60324
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.484
Heterozygous variant carriers
0
2318
4636
6953
9271
11589
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
982
1964
2946
3928
4910
<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:
0.0215
AC:
3274
AN:
152036
Hom.:
66
Cov.:
32
AF XY:
0.0220
AC XY:
1638
AN XY:
74308
show subpopulations
African (AFR)
AF:
0.00465
AC:
193
AN:
41536
American (AMR)
AF:
0.0233
AC:
356
AN:
15258
Ashkenazi Jewish (ASJ)
AF:
0.0193
AC:
67
AN:
3470
East Asian (EAS)
AF:
0.0953
AC:
488
AN:
5120
South Asian (SAS)
AF:
0.00892
AC:
43
AN:
4820
European-Finnish (FIN)
AF:
0.0450
AC:
477
AN:
10604
Middle Eastern (MID)
AF:
0.0136
AC:
4
AN:
294
European-Non Finnish (NFE)
AF:
0.0231
AC:
1572
AN:
67910
Other (OTH)
AF:
0.0218
AC:
46
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.498
Heterozygous variant carriers
0
171
342
512
683
854
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
40
80
120
160
200
<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:
0.0211
Hom.:
52
Bravo
AF:
0.0200
Asia WGS
AF:
0.0360
AC:
125
AN:
3476
EpiCase
AF:
0.0201
EpiControl
AF:
0.0219

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:23
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:10
Apr 29, 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. -

Apr 26, 2012
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Asp15039Asp in TTN: This variant is not expected to have clinical significance b ecause it does not alter an amino acid residue. It has been identified in 2.2% ( 150/6746) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; rs2303831). Asp15 039Asp in TTN (rs2303831; allele frequency = 2.2%, 150/6746) ** -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
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

- -

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

- -

-
PreventionGenetics, part of Exact Sciences
Significance: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

BA1 -

Jan 11, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Benign
Review Status:no assertion criteria provided
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: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 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. -

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

- -

Jan 16, 2019
Athena Diagnostics
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 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. -

Tibial muscular dystrophy Benign:2
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. -

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

- -

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. -

Cardiovascular phenotype Benign:1
Feb 04, 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
BayesDel_noAF
Benign
-0.46
CADD
Benign
1.1
DANN
Benign
0.76
PhyloP100
1.1
Mutation Taster
=32/68
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: rs2303831; hg19: chr2-179472693; COSMIC: COSV60187895; COSMIC: COSV60187895; API