chr2-178539823-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001267550.2(TTN):​c.98242C>T​(p.Arg32748Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00346 in 1,613,820 control chromosomes in the GnomAD database, including 17 homozygotes. 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 0.0036 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0034 ( 15 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

4
6
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:20

Conservation

PhyloP100: 3.92
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 made for transcript

Verdict is Benign. Variant got -12 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=0.00862062).
BP6
Variant 2-178539823-G-A is Benign according to our data. Variant chr2-178539823-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47596.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=9, Uncertain_significance=4}. Variant chr2-178539823-G-A is described in Lovd as [Benign]. Variant chr2-178539823-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0036 (548/152260) while in subpopulation NFE AF= 0.00556 (378/68022). AF 95% confidence interval is 0.0051. There are 2 homozygotes in gnomad4. There are 295 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TTNNM_001267550.2 linkuse as main transcriptc.98242C>T p.Arg32748Cys missense_variant 352/363 ENST00000589042.5 NP_001254479.2
TTN-AS1NR_038272.1 linkuse as main transcriptn.1773G>A non_coding_transcript_exon_variant 5/17

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkuse as main transcriptc.98242C>T p.Arg32748Cys missense_variant 352/3635 NM_001267550.2 ENSP00000467141 P1
TTN-AS1ENST00000659121.1 linkuse as main transcriptn.416+16187G>A intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.00360
AC:
548
AN:
152142
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000507
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.00118
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00270
Gnomad FIN
AF:
0.0106
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00556
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00374
AC:
932
AN:
248880
Hom.:
1
AF XY:
0.00386
AC XY:
521
AN XY:
135006
show subpopulations
Gnomad AFR exome
AF:
0.000258
Gnomad AMR exome
AF:
0.000522
Gnomad ASJ exome
AF:
0.00119
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00274
Gnomad FIN exome
AF:
0.00966
Gnomad NFE exome
AF:
0.00525
Gnomad OTH exome
AF:
0.00232
GnomAD4 exome
AF:
0.00344
AC:
5035
AN:
1461560
Hom.:
15
Cov.:
33
AF XY:
0.00344
AC XY:
2503
AN XY:
727058
show subpopulations
Gnomad4 AFR exome
AF:
0.000329
Gnomad4 AMR exome
AF:
0.000626
Gnomad4 ASJ exome
AF:
0.000842
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00220
Gnomad4 FIN exome
AF:
0.00865
Gnomad4 NFE exome
AF:
0.00371
Gnomad4 OTH exome
AF:
0.00300
GnomAD4 genome
AF:
0.00360
AC:
548
AN:
152260
Hom.:
2
Cov.:
32
AF XY:
0.00396
AC XY:
295
AN XY:
74434
show subpopulations
Gnomad4 AFR
AF:
0.000505
Gnomad4 AMR
AF:
0.00118
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00270
Gnomad4 FIN
AF:
0.0106
Gnomad4 NFE
AF:
0.00556
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.00446
Hom.:
4
Bravo
AF:
0.00223
TwinsUK
AF:
0.00243
AC:
9
ALSPAC
AF:
0.00234
AC:
9
ESP6500AA
AF:
0.000495
AC:
2
ESP6500EA
AF:
0.00407
AC:
34
ExAC
AF:
0.00404
AC:
488
Asia WGS
AF:
0.00173
AC:
6
AN:
3478
EpiCase
AF:
0.00387
EpiControl
AF:
0.00356

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:20
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:8
Benign, criteria provided, single submitterclinical testingGeneDxAug 23, 2016This 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. -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 10, 2015p.Arg30180Cys in exon 301 of TTN: This variant is not expected to have clinical significance because it has been identified in 1.2% (76/6606) of Finnish chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs72648272). -
Likely benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 02, 2015- -
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJun 03, 2014- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsOct 09, 2019- -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 30, 2022- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
not provided Benign:6
Likely benign, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJun 24, 2013- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 31, 2023- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2024TTN: BS2 -
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. -
TTN-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 13, 2020This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Cardiomyopathy Benign:1
Benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioOct 29, 2019- -
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
Benign, criteria provided, single submitterclinical testingAmbry GeneticsFeb 15, 2016This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.40
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.22
CADD
Uncertain
24
DANN
Benign
0.94
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.95
D;D;D;.;D;D;D
MetaRNN
Benign
0.0086
T;T;T;T;T;T;T
MetaSVM
Benign
-0.39
T
MutationAssessor
Pathogenic
3.1
.;.;.;M;.;.;M
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.62
T
PROVEAN
Pathogenic
-5.8
D;D;.;.;D;D;.
REVEL
Uncertain
0.35
Sift
Uncertain
0.0030
D;D;.;.;D;D;.
Polyphen
1.0
.;.;.;D;.;.;D
Vest4
0.52
MVP
0.63
MPC
0.54
ClinPred
0.085
T
GERP RS
5.2

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
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: rs72648272; hg19: chr2-179404550; API