chr2-178562809-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001267550.2(TTN):​c.83323A>G​(p.Ile27775Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,612,474 control chromosomes in the GnomAD database, including 74,712 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I27775T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.36 ( 11855 hom., cov: 33)
Exomes 𝑓: 0.27 ( 62857 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

16

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24

Conservation

PhyloP100: 0.477

Publications

46 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=4.253756E-6).
BP6
Variant 2-178562809-T-C is Benign according to our data. Variant chr2-178562809-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.681 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.83323A>G p.Ile27775Val 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.83323A>G p.Ile27775Val missense_variant Exon 326 of 363 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.362
AC:
54920
AN:
151850
Hom.:
11806
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.541
Gnomad AMI
AF:
0.560
Gnomad AMR
AF:
0.384
Gnomad ASJ
AF:
0.284
Gnomad EAS
AF:
0.700
Gnomad SAS
AF:
0.516
Gnomad FIN
AF:
0.285
Gnomad MID
AF:
0.275
Gnomad NFE
AF:
0.225
Gnomad OTH
AF:
0.328
GnomAD2 exomes
AF:
0.352
AC:
86795
AN:
246406
AF XY:
0.349
show subpopulations
Gnomad AFR exome
AF:
0.545
Gnomad AMR exome
AF:
0.426
Gnomad ASJ exome
AF:
0.281
Gnomad EAS exome
AF:
0.704
Gnomad FIN exome
AF:
0.277
Gnomad NFE exome
AF:
0.226
Gnomad OTH exome
AF:
0.308
GnomAD4 exome
AF:
0.269
AC:
392178
AN:
1460506
Hom.:
62857
Cov.:
40
AF XY:
0.274
AC XY:
198713
AN XY:
726470
show subpopulations
African (AFR)
AF:
0.556
AC:
18602
AN:
33458
American (AMR)
AF:
0.425
AC:
18935
AN:
44544
Ashkenazi Jewish (ASJ)
AF:
0.280
AC:
7303
AN:
26116
East Asian (EAS)
AF:
0.694
AC:
27427
AN:
39530
South Asian (SAS)
AF:
0.504
AC:
43445
AN:
86222
European-Finnish (FIN)
AF:
0.277
AC:
14763
AN:
53294
Middle Eastern (MID)
AF:
0.307
AC:
1771
AN:
5768
European-Non Finnish (NFE)
AF:
0.217
AC:
241659
AN:
1111286
Other (OTH)
AF:
0.303
AC:
18273
AN:
60288
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
16961
33922
50882
67843
84804
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
8910
17820
26730
35640
44550
<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:
0.362
AC:
55030
AN:
151968
Hom.:
11855
Cov.:
33
AF XY:
0.372
AC XY:
27638
AN XY:
74304
show subpopulations
African (AFR)
AF:
0.542
AC:
22461
AN:
41434
American (AMR)
AF:
0.384
AC:
5864
AN:
15254
Ashkenazi Jewish (ASJ)
AF:
0.284
AC:
986
AN:
3468
East Asian (EAS)
AF:
0.701
AC:
3595
AN:
5132
South Asian (SAS)
AF:
0.514
AC:
2479
AN:
4822
European-Finnish (FIN)
AF:
0.285
AC:
3022
AN:
10586
Middle Eastern (MID)
AF:
0.286
AC:
84
AN:
294
European-Non Finnish (NFE)
AF:
0.225
AC:
15318
AN:
67952
Other (OTH)
AF:
0.336
AC:
711
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.503
Heterozygous variant carriers
0
1648
3297
4945
6594
8242
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
520
1040
1560
2080
2600
<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:
0.280
Hom.:
23953
Bravo
AF:
0.376
TwinsUK
AF:
0.214
AC:
792
ALSPAC
AF:
0.216
AC:
834
ESP6500AA
AF:
0.532
AC:
2013
ESP6500EA
AF:
0.223
AC:
1841
ExAC
AF:
0.350
AC:
42293
Asia WGS
AF:
0.618
AC:
2146
AN:
3476

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:24
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:11
Sep 27, 2011
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
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

- -

Aug 15, 2013
Genetic Services Laboratory, University of Chicago
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

- -

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

- -

Aug 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

- -

Oct 31, 2012
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. -

Jul 23, 2013
Eurofins Ntd Llc (ga)
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

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
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

BA1 -

Autosomal recessive limb-girdle muscular dystrophy type 2J 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

- -

Early-onset myopathy with fatal cardiomyopathy 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

- -

not provided Benign:2
Nov 02, 2018
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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

- -

Myopathy, myofibrillar, 9, with early respiratory failure 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

- -

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

- -

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
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
Benign
0.054
BayesDel_addAF
Benign
-0.78
T
BayesDel_noAF
Benign
-0.74
CADD
Benign
7.9
DANN
Benign
0.86
Eigen
Benign
-0.69
Eigen_PC
Benign
-0.48
FATHMM_MKL
Benign
0.029
N
LIST_S2
Benign
0.59
T;T;T;.;T;T;T
MetaRNN
Benign
0.0000043
T;T;T;T;T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
-0.54
.;.;.;N;.;.;N
PhyloP100
0.48
PrimateAI
Benign
0.39
T
PROVEAN
Benign
0.40
N;N;.;.;N;N;.
REVEL
Benign
0.12
Sift
Benign
1.0
T;T;.;.;T;T;.
Polyphen
0.0
.;.;.;B;.;.;B
Vest4
0.048
MPC
0.070
ClinPred
0.0010
T
GERP RS
5.2
Mutation Taster
=100/0
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: rs3829746; hg19: chr2-179427536; COSMIC: COSV60156917; COSMIC: COSV60156917; API