chr2-178541317-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001267550.2(TTN):​c.97760G>A​(p.Arg32587His) variant causes a missense change. The variant allele was found at a frequency of 0.00272 in 1,546,330 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 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. R32587P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0030 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0027 ( 4 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

7
10

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 3.85
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 Benign. Variant got -19 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=0.0072649717).
BP6
Variant 2-178541317-C-T is Benign according to our data. Variant chr2-178541317-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 47588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178541317-C-T is described in Lovd as [Benign]. Variant chr2-178541317-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00303 (461/152250) while in subpopulation AFR AF= 0.00448 (186/41536). AF 95% confidence interval is 0.00395. There are 1 homozygotes in gnomad4. There are 203 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TTNNM_001267550.2 linkuse as main transcriptc.97760G>A p.Arg32587His missense_variant 350/363 ENST00000589042.5 NP_001254479.2
TTN-AS1NR_038272.1 linkuse as main transcriptn.1904-905C>T 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.97760G>A p.Arg32587His missense_variant 350/3635 NM_001267550.2 ENSP00000467141 P1
ENST00000604692.1 linkuse as main transcriptn.193C>T non_coding_transcript_exon_variant 1/1
TTN-AS1ENST00000659121.1 linkuse as main transcriptn.416+17681C>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.00302
AC:
460
AN:
152132
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00447
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00203
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000471
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00341
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.00173
AC:
291
AN:
167792
Hom.:
0
AF XY:
0.00145
AC XY:
128
AN XY:
88462
show subpopulations
Gnomad AFR exome
AF:
0.00324
Gnomad AMR exome
AF:
0.00148
Gnomad ASJ exome
AF:
0.000356
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000217
Gnomad FIN exome
AF:
0.000581
Gnomad NFE exome
AF:
0.00289
Gnomad OTH exome
AF:
0.00174
GnomAD4 exome
AF:
0.00269
AC:
3751
AN:
1394080
Hom.:
4
Cov.:
31
AF XY:
0.00260
AC XY:
1788
AN XY:
686982
show subpopulations
Gnomad4 AFR exome
AF:
0.00462
Gnomad4 AMR exome
AF:
0.00213
Gnomad4 ASJ exome
AF:
0.000121
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000243
Gnomad4 FIN exome
AF:
0.000961
Gnomad4 NFE exome
AF:
0.00310
Gnomad4 OTH exome
AF:
0.00213
GnomAD4 genome
AF:
0.00303
AC:
461
AN:
152250
Hom.:
1
Cov.:
33
AF XY:
0.00273
AC XY:
203
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.00448
Gnomad4 AMR
AF:
0.00203
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000471
Gnomad4 NFE
AF:
0.00341
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.00163
Hom.:
1
Bravo
AF:
0.00305
TwinsUK
AF:
0.00405
AC:
15
ALSPAC
AF:
0.00311
AC:
12
ESP6500AA
AF:
0.00362
AC:
14
ESP6500EA
AF:
0.00376
AC:
31
ExAC
AF:
0.00158
AC:
186
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:5
Likely benign, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJun 24, 2013- -
Benign, criteria provided, single submitterclinical testingGeneDxJun 03, 2020This variant is associated with the following publications: (PMID: 18948003, 1745277, 12669942, 23861362, 24105469, 24395473, 21810661, 22335739, 23418287, 23518707, 21617319, 10462489, 11717165, 12145747, 17444505) -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2024TTN: BS1 -
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJun 15, 2017- -
Likely benign, criteria provided, single submittercurationARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesDec 19, 2023- -
not specified Benign:4
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineSep 14, 2015p.Arg30019His in exon 299 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.5% (61/10980) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs55704830). -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 08, 2020Variant summary: TTN c.90056G>A (p.Arg30019His) results in a non-conservative amino acid change located in the A- band region (cardiodb.org) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 167792 control chromosomes. The observed variant frequency is approximately 4.4- fold the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is benign. c.90056G>A has been reported in the literature in at least one individual affected with Dilated Cardiomyopathy without strong evidence for causality (e.g. Headrick_2018). This report does 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. 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (uncetain significance, n=3; benign/likely benign, n=8). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 30, 2015- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsMar 19, 2021- -
Cardiomyopathy Benign:2
Benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioJan 27, 2020- -
Likely benign, criteria provided, single submitterclinical testingCenter for Advanced Laboratory Medicine, UC San Diego Health, University of California San DiegoDec 06, 2017- -
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- -
Tibial muscular dystrophy Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJul 25, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Myopathy, myofibrillar, 9, with early respiratory failure Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJul 25, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 01, 2018This 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
0.091
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
22
DANN
Benign
0.97
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.94
D;D;D;.;D;D;D
M_CAP
Uncertain
0.093
D
MetaRNN
Benign
0.0073
T;T;T;T;T;T;T
MetaSVM
Benign
-0.79
T
MutationAssessor
Benign
0.94
.;.;.;L;.;.;L
MutationTaster
Benign
0.96
D;D;D;D;D;D
PrimateAI
Uncertain
0.55
T
PROVEAN
Uncertain
-3.0
D;D;.;.;D;D;.
REVEL
Benign
0.21
Sift
Benign
0.059
T;T;.;.;T;T;.
Polyphen
1.0
.;.;.;D;.;.;D
Vest4
0.37
MVP
0.21
MPC
0.36
ClinPred
0.019
T
GERP RS
5.7

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: rs55704830; hg19: chr2-179406044; COSMIC: COSV60286041; COSMIC: COSV60286041; API