2-178709854-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4BP6

The NM_001267550.2(TTN):​c.28465C>T​(p.Arg9489Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000597 in 1,607,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense, splice_region

Scores

4
4
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 5.86
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 made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TTN. . Gene score misZ -1.1021 (greater than the threshold 3.09). Trascript score misZ 6.9794 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, tibial muscular dystrophy, early-onset myopathy with fatal cardiomyopathy, autosomal recessive centronuclear myopathy, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 9, TTN-related myopathy, dilated cardiomyopathy 1G, arrhythmogenic right ventricular cardiomyopathy, myopathy, myofibrillar, 9, with early respiratory failure, familial isolated dilated cardiomyopathy, childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome, autosomal recessive limb-girdle muscular dystrophy type 2J.
BP4
Computational evidence support a benign effect (MetaRNN=0.32937592).
BP6
Variant 2-178709854-G-A is Benign according to our data. Variant chr2-178709854-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 192001.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=7}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TTNNM_001267550.2 linkuse as main transcriptc.28465C>T p.Arg9489Trp missense_variant, splice_region_variant 99/363 ENST00000589042.5 NP_001254479.2
LOC124906100XR_007087318.1 linkuse as main transcriptn.2186-3900G>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkuse as main transcriptc.28465C>T p.Arg9489Trp missense_variant, splice_region_variant 99/3635 NM_001267550.2 ENSP00000467141 P1
TTN-AS1ENST00000659121.1 linkuse as main transcriptn.503-24650G>A intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
151982
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000484
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000486
AC:
12
AN:
246722
Hom.:
0
AF XY:
0.0000597
AC XY:
8
AN XY:
133930
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000559
Gnomad SAS exome
AF:
0.0000995
Gnomad FIN exome
AF:
0.0000480
Gnomad NFE exome
AF:
0.0000534
Gnomad OTH exome
AF:
0.000168
GnomAD4 exome
AF:
0.0000618
AC:
90
AN:
1455324
Hom.:
0
Cov.:
31
AF XY:
0.0000705
AC XY:
51
AN XY:
723210
show subpopulations
Gnomad4 AFR exome
AF:
0.0000301
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000221
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000614
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000395
AC:
6
AN:
151982
Hom.:
0
Cov.:
33
AF XY:
0.0000539
AC XY:
4
AN XY:
74242
show subpopulations
Gnomad4 AFR
AF:
0.0000484
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000566
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000331
AC:
4

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJun 12, 2018- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 24, 2015Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in CARDIOMYOPATHY panel(s). -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJun 24, 2013- -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 20, 2022- -
Autosomal recessive limb-girdle muscular dystrophy type 2J Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Early-onset myopathy with fatal cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Myopathy, myofibrillar, 9, with early respiratory failure Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.32
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
23
DANN
Benign
0.97
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
D;D;.;D
M_CAP
Benign
0.050
D
MetaRNN
Benign
0.33
T;T;T;T
MetaSVM
Benign
-0.31
T
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-5.2
D;.;.;.
REVEL
Uncertain
0.43
Sift
Uncertain
0.0030
D;.;.;.
Polyphen
1.0
.;.;D;D
Vest4
0.28
MutPred
0.53
.;.;Loss of disorder (P = 0.0171);Loss of disorder (P = 0.0171);
MVP
0.38
MPC
0.47
ClinPred
0.55
D
GERP RS
5.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200489972; hg19: chr2-179574581; API