2-178794464-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBP6

The NM_001267550.2(TTN):​c.1333G>A​(p.Ala445Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,614,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

5
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:5

Conservation

PhyloP100: 1.65
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 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=0.027612716).
BP6
Variant 2-178794464-C-T is Benign according to our data. Variant chr2-178794464-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178276.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=9, Likely_benign=3}. Variant chr2-178794464-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TTNNM_001267550.2 linkuse as main transcriptc.1333G>A p.Ala445Thr missense_variant 8/363 ENST00000589042.5 NP_001254479.2
TTNNM_133379.5 linkuse as main transcriptc.1333G>A p.Ala445Thr missense_variant 8/46 ENST00000360870.10 NP_596870.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkuse as main transcriptc.1333G>A p.Ala445Thr missense_variant 8/3635 NM_001267550.2 ENSP00000467141 P1
TTNENST00000360870.10 linkuse as main transcriptc.1333G>A p.Ala445Thr missense_variant 8/465 NM_133379.5 ENSP00000354117 Q8WZ42-6

Frequencies

GnomAD3 genomes
AF:
0.000263
AC:
40
AN:
152220
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000723
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.00231
Gnomad EAS
AF:
0.00154
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000191
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000219
AC:
55
AN:
251358
Hom.:
0
AF XY:
0.000250
AC XY:
34
AN XY:
135844
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000434
Gnomad ASJ exome
AF:
0.00169
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000150
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.000292
AC:
427
AN:
1461856
Hom.:
0
Cov.:
32
AF XY:
0.000303
AC XY:
220
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000380
Gnomad4 ASJ exome
AF:
0.00199
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000290
Gnomad4 OTH exome
AF:
0.000414
GnomAD4 genome
AF:
0.000263
AC:
40
AN:
152338
Hom.:
0
Cov.:
33
AF XY:
0.000228
AC XY:
17
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.0000721
Gnomad4 AMR
AF:
0.000392
Gnomad4 ASJ
AF:
0.00231
Gnomad4 EAS
AF:
0.00154
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000191
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000223
Hom.:
0
Bravo
AF:
0.000246
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000581
AC:
5
ExAC
AF:
0.000231
AC:
28
Asia WGS
AF:
0.000867
AC:
3
AN:
3476
EpiCase
AF:
0.000273
EpiControl
AF:
0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3Benign:2
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 11, 2021This variant is associated with the following publications: (PMID: 30847666) -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityMar 14, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 24, 2018- -
Likely benign, criteria provided, single submitterclinical testingAthena DiagnosticsJan 07, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2024- -
not specified Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 26, 2013The Ala445Thr variant in TTN has not been previously reported in individuals wit h cardiomyopathy, but has been identified in 5/8600 European American chromosome s by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu; dbSNP rs1 42414432). Computational analyses (amino acid biochemical properties, conservat ion, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or agains t an impact to the protein. Additional information is needed to fully assess the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 15, 2023Variant summary: TTN c.1333G>A (p.Ala445Thr) results in a non-conservative amino acid change located in the Z-disk region of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 251358 control chromosomes (gnomAD), predominantly at a frequency of 0.00043 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.1 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), suggesting that the variant may be a benign polymorphism found primarily in populations of Latino origin. c.1333G>A has been reported in the literature in individuals affected with Cardiomyopathy (Campuzano_2015, van Lint_2019, Guelly_2021) . These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26516846, 33552729, 30847666). Eight ClinVar submitters have assessed the variant since 2014: four classified the variant as uncertain significance, three as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
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. -
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 19, 2017- -
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. -
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. -
Myopathy, myofibrillar, 9, with early respiratory failure 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. -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsOct 18, 2019This alteration is classified as likely 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.097
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.37
CADD
Uncertain
24
DANN
Benign
0.97
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Benign
0.85
T;D;D;.;D;D;T;D;D
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.028
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.84
T
MutationTaster
Benign
0.70
D;N;N;N;N;N;N
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-1.9
N;N;.;.;N;N;.;N;D
REVEL
Benign
0.15
Sift
Benign
0.14
T;T;.;.;T;T;.;D;D
Sift4G
Uncertain
0.056
.;.;.;.;.;.;.;T;.
Polyphen
0.98, 1.0
.;.;.;D;.;.;D;D;.
Vest4
0.39
MVP
0.21
MPC
0.23
ClinPred
0.061
T
GERP RS
5.9

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

LitVar

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

Other links and lift over

dbSNP: rs142414432; hg19: chr2-179659191; COSMIC: COSV100594405; COSMIC: COSV100594405; API