2-178739264-T-G
Variant names:
Variant summary
Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001267550.2(TTN):c.13969A>C(p.Asn4657His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,610,242 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00091 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0016 ( 32 hom. )
Consequence
TTN
NM_001267550.2 missense
NM_001267550.2 missense
Scores
4
10
Clinical Significance
Conservation
PhyloP100: 3.45
Publications
9 publications found
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 -13 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.006801218).
BP6
Variant 2-178739264-T-G is Benign according to our data. Variant chr2-178739264-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47843.
BS1
Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000912 (139/152336) while in subpopulation SAS AF = 0.0157 (76/4830). AF 95% confidence interval is 0.0129. There are 1 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAdExome4 at 32 AD,AR gene
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | MANE Select | c.13969A>C | p.Asn4657His | missense | Exon 48 of 363 | NP_001254479.2 | ||
| TTN | NM_001256850.1 | c.13018A>C | p.Asn4340His | missense | Exon 46 of 313 | NP_001243779.1 | |||
| TTN | NM_133437.4 | c.13456A>C | p.Asn4486His | missense | Exon 46 of 192 | NP_597681.4 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | TSL:5 MANE Select | c.13969A>C | p.Asn4657His | missense | Exon 48 of 363 | ENSP00000467141.1 | ||
| TTN | ENST00000446966.2 | TSL:1 | c.13969A>C | p.Asn4657His | missense | Exon 48 of 361 | ENSP00000408004.2 | ||
| TTN | ENST00000436599.2 | TSL:1 | c.13693A>C | p.Asn4565His | missense | Exon 46 of 361 | ENSP00000405517.2 |
Frequencies
GnomAD3 genomes 0.000900 AC: 137AN: 152218Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
137
AN:
152218
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD2 exomes AF: 0.00275 AC: 679AN: 247146 AF XY: 0.00363 show subpopulations
GnomAD2 exomes
AF:
AC:
679
AN:
247146
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00159 AC: 2318AN: 1457906Hom.: 32 Cov.: 31 AF XY: 0.00212 AC XY: 1533AN XY: 724562 show subpopulations
GnomAD4 exome
AF:
AC:
2318
AN:
1457906
Hom.:
Cov.:
31
AF XY:
AC XY:
1533
AN XY:
724562
show subpopulations
African (AFR)
AF:
AC:
4
AN:
33396
American (AMR)
AF:
AC:
15
AN:
44594
Ashkenazi Jewish (ASJ)
AF:
AC:
24
AN:
26016
East Asian (EAS)
AF:
AC:
0
AN:
39508
South Asian (SAS)
AF:
AC:
1466
AN:
86028
European-Finnish (FIN)
AF:
AC:
1
AN:
53274
Middle Eastern (MID)
AF:
AC:
32
AN:
5754
European-Non Finnish (NFE)
AF:
AC:
691
AN:
1109144
Other (OTH)
AF:
AC:
85
AN:
60192
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.498
Heterozygous variant carriers
0
131
261
392
522
653
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Exome 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
GnomAD4 genome 0.000912 AC: 139AN: 152336Hom.: 1 Cov.: 32 AF XY: 0.00124 AC XY: 92AN XY: 74488 show subpopulations
GnomAD4 genome
AF:
AC:
139
AN:
152336
Hom.:
Cov.:
32
AF XY:
AC XY:
92
AN XY:
74488
show subpopulations
African (AFR)
AF:
AC:
4
AN:
41584
American (AMR)
AF:
AC:
6
AN:
15298
Ashkenazi Jewish (ASJ)
AF:
AC:
1
AN:
3470
East Asian (EAS)
AF:
AC:
0
AN:
5176
South Asian (SAS)
AF:
AC:
76
AN:
4830
European-Finnish (FIN)
AF:
AC:
5
AN:
10632
Middle Eastern (MID)
AF:
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
AC:
44
AN:
68026
Other (OTH)
AF:
AC:
1
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
8
16
23
31
39
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Genome Het
Variant carriers
0
10
20
30
40
50
<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:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
4
ALSPAC
AF:
AC:
1
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
5
ExAC
AF:
AC:
376
Asia WGS
AF:
AC:
11
AN:
3476
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:11
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:7
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:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Mar 19, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The Asn4419His variant in TTN has been identified by our laboratory in 3 individ uals with cardiomyopathy (1 with DCM and 2 with HCM). It has also been identifie d in 5/8238 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs200204761). Computational predictions are limited or unavailable for this variant. Additional information is needed t o fully assess the clinical significance of this variant.
Feb 02, 2024
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Sep 02, 2016
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.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
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
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 Uncertain:1
Jun 24, 2013
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Cardiomyopathy Benign:1
Feb 27, 2018
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Hypertrophic cardiomyopathy Benign:1
Jun 15, 2018
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Cardiovascular phenotype Benign:1
Sep 12, 2019
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: seen in unaffected individuals, 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
DANN
Benign
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
PhyloP100
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Benign
T
Vest4
MVP
MPC
ClinPred
T
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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