chr2-178731466-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2BP4_StrongBP6_Very_Strong

The NM_001267550.2(TTN):​c.17300G>A​(p.Ser5767Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,613,736 control chromosomes in the GnomAD database, including 1 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S5767S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

1
15

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 2.27
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 -11 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=0.0033086836).
BP6
Variant 2-178731466-C-T is Benign according to our data. Variant chr2-178731466-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TTNNM_001267550.2 linkuse as main transcriptc.17300G>A p.Ser5767Asn missense_variant 59/363 ENST00000589042.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TTNENST00000589042.5 linkuse as main transcriptc.17300G>A p.Ser5767Asn missense_variant 59/3635 NM_001267550.2 P1
TTN-AS1ENST00000659121.1 linkuse as main transcriptn.503-3038C>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.000992
AC:
151
AN:
152144
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00352
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000314
AC:
78
AN:
248614
Hom.:
0
AF XY:
0.000274
AC XY:
37
AN XY:
134880
show subpopulations
Gnomad AFR exome
AF:
0.00465
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000794
AC:
116
AN:
1461474
Hom.:
0
Cov.:
36
AF XY:
0.0000509
AC XY:
37
AN XY:
727012
show subpopulations
Gnomad4 AFR exome
AF:
0.00278
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.000215
GnomAD4 genome
AF:
0.00102
AC:
155
AN:
152262
Hom.:
1
Cov.:
32
AF XY:
0.00113
AC XY:
84
AN XY:
74446
show subpopulations
Gnomad4 AFR
AF:
0.00361
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000204
Hom.:
0
Bravo
AF:
0.00120
ESP6500AA
AF:
0.00494
AC:
19
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000381
AC:
46
Asia WGS
AF:
0.000867
AC:
3
AN:
3476

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsOct 28, 2016- -
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 24, 2012p.Ser4523Asn in exon 56 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 0.4% (13/3160) of African American chromosomes by the NHLBI Exome Sequencing Project in a broad population (http:// evs.gs.washington.edu/EVS). -
Likely benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 21, 2015- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 08, 2022Variant summary: TTN c.13568G>A (p.Ser4523Asn) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 248614 control chromosomes, predominantly at a frequency of 0.0047 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 12-fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.13568G>A has been reported in the literature in individual(s) affected with Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (Fedida_2017). These report(s) 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. Six ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
not provided Benign:3
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 16, 2020- -
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJul 10, 2021- -
Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 10, 2021- -
TTN-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJan 27, 2021This 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
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 24, 2024- -
Early-onset myopathy with fatal cardiomyopathy Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 10, 2021- -
Tibial muscular dystrophy Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 10, 2021- -
Myopathy, myofibrillar, 9, with early respiratory failure Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 10, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.053
BayesDel_addAF
Benign
-0.62
T
BayesDel_noAF
Benign
-0.66
CADD
Benign
16
DANN
Benign
0.87
Eigen
Benign
-0.61
Eigen_PC
Benign
-0.39
FATHMM_MKL
Benign
0.28
N
LIST_S2
Benign
0.39
T;T;.;T
M_CAP
Benign
0.032
D
MetaRNN
Benign
0.0033
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
1.0
D;D;D;N;N;N
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
1.6
N;.;.;.
REVEL
Benign
0.049
Sift
Benign
0.79
T;.;.;.
Polyphen
0.0
.;.;B;B
Vest4
0.067
MVP
0.030
MPC
0.078
ClinPred
0.0074
T
GERP RS
4.4

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: rs200692495; hg19: chr2-179596193; COSMIC: COSV60200886; COSMIC: COSV60200886; API