rs202011992

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBP6

The NM_001267550.2(TTN):ā€‹c.9674A>Gā€‹(p.Asn3225Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000991 in 1,613,868 control chromosomes in the GnomAD database, including 1 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: š‘“ 0.000059 ( 0 hom., cov: 32)
Exomes š‘“: 0.00010 ( 1 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

1
6
10

Clinical Significance

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

Conservation

PhyloP100: 7.67
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 -2 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=0.19854188).
BP6
Variant 2-178766410-T-C is Benign according to our data. Variant chr2-178766410-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47673.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TTNNM_001267550.2 linkuse as main transcriptc.9674A>G p.Asn3225Ser missense_variant 41/363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7
TTNNM_133379.5 linkuse as main transcriptc.9674A>G p.Asn3225Ser missense_variant 41/46 ENST00000360870.10 NP_596870.2 Q8WZ42-6Q7Z3B7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkuse as main transcriptc.9674A>G p.Asn3225Ser missense_variant 41/3635 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7
TTNENST00000360870.10 linkuse as main transcriptc.9674A>G p.Asn3225Ser missense_variant 41/465 NM_133379.5 ENSP00000354117.4 Q8WZ42-6

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152186
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000398
AC:
10
AN:
251220
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135770
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000103
AC:
151
AN:
1461682
Hom.:
1
Cov.:
31
AF XY:
0.000100
AC XY:
73
AN XY:
727166
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
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:
0.000127
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152186
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000154
Hom.:
0
Bravo
AF:
0.0000642
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

not provided Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvitySep 28, 2022- -
Uncertain significance, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJun 24, 2013- -
Likely benign, criteria provided, single submitterclinical testingGeneDxOct 02, 2020This variant is associated with the following publications: (PMID: 24503780, 31983221) -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Feb 06, 2017- -
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 27, 2018The p.Asn3225Ser variant in TTN is classified as likely benign because it has be en identified 0.01% (11/126504) of European chromosomes by the Genome Aggregatio n Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs202011992). In add ition, this variant was identified by this laboratory in 2 individuals who carri ed other variants sufficient to explain their cardiomyopathy. One carried a like ly pathogenic variant in TTN and the other carried a likely pathogenic ATCT1 var iant. ACMG/AMP Criteria applied: BS1_Supporting; BP2; BP5. -
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoMay 06, 2020The c.9674A>G sequence change results in an amino acid change, p.Asn3225Ser. This sequence change has been described in the gnomAD database with a low population frequency of 0.00426% (dbSNP rs202011992). The p.Asn3225Ser change affects a highly conserved amino acid residue located in a domain of the TTN protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asn3225Ser substitution. This sequence change does not appear to have been previously described in patients with TTN-related disorders. Due to lack of sufficient evidence, the clinical significance of the p.Asn3225Ser change remains unknown at this time. -
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 30, 2017- -
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioMay 20, 2016- -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 12, 2019The p.N3179S variant (also known as c.9536A>G), located in coding exon 39 of the TTN gene, results from an A to G substitution at nucleotide position 9536. The asparagine at codon 3179 is replaced by serine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.34
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
22
DANN
Benign
0.97
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D;D;D;.;D;D;D;D
M_CAP
Benign
0.023
T
MetaRNN
Benign
0.20
T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-3.1
D;D;.;.;D;D;.;D
REVEL
Benign
0.20
Sift
Benign
0.68
T;T;.;.;T;T;.;T
Sift4G
Uncertain
0.021
.;.;.;.;.;.;.;D
Polyphen
0.91, 0.95
.;.;.;P;.;.;P;P
Vest4
0.26
MVP
0.13
MPC
0.14
ClinPred
0.20
T
GERP RS
5.6

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: rs202011992; hg19: chr2-179631137; API