rs28933405

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP5

The NM_001267550.2(TTN):​c.2219G>T​(p.Arg740Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R740S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

4
13

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.627
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 Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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.
PP5
Variant 2-178785999-C-A is Pathogenic according to our data. Variant chr2-178785999-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 12649.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-178785999-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TTNNM_001267550.2 linkuse as main transcriptc.2219G>T p.Arg740Leu missense_variant 14/363 ENST00000589042.5
TTNNM_133379.5 linkuse as main transcriptc.2219G>T p.Arg740Leu missense_variant 14/46 ENST00000360870.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TTNENST00000589042.5 linkuse as main transcriptc.2219G>T p.Arg740Leu missense_variant 14/3635 NM_001267550.2 P1
TTNENST00000360870.10 linkuse as main transcriptc.2219G>T p.Arg740Leu missense_variant 14/465 NM_133379.5 Q8WZ42-6

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461822
Hom.:
0
Cov.:
35
AF XY:
0.00000138
AC XY:
1
AN XY:
727212
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 9 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 27, 1999- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Uncertain
0.068
T
BayesDel_noAF
Benign
-0.14
CADD
Benign
8.0
DANN
Benign
0.36
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.66
D
LIST_S2
Uncertain
0.87
D;D;D;.;D;D;T;D
M_CAP
Benign
0.029
D
MetaRNN
Uncertain
0.56
D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.95
T
MutationTaster
Benign
0.0000031
A;A;A;A;A;A;A
PrimateAI
Benign
0.22
T
PROVEAN
Benign
-2.0
N;N;.;.;N;N;.;N
REVEL
Uncertain
0.32
Sift
Benign
0.067
T;D;.;.;T;T;.;D
Sift4G
Benign
0.45
.;.;.;.;.;.;.;T
Polyphen
0.0, 0.0010
.;.;.;B;.;.;B;B
Vest4
0.51
MutPred
0.47
Loss of phosphorylation at S742 (P = 0.0497);.;Loss of phosphorylation at S742 (P = 0.0497);Loss of phosphorylation at S742 (P = 0.0497);.;.;Loss of phosphorylation at S742 (P = 0.0497);Loss of phosphorylation at S742 (P = 0.0497);
MVP
0.21
MPC
0.10
ClinPred
0.074
T
GERP RS
1.2

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: rs28933405; hg19: chr2-179650726; API