rs370918800

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001267550.2(TTN):​c.94774G>C​(p.Val31592Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V31592I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

TTN
NM_001267550.2 missense

Scores

5
12

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.96
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 Uncertain_significance. Variant got 2 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.31219095).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TTNNM_001267550.2 linkuse as main transcriptc.94774G>C p.Val31592Leu missense_variant 341/363 ENST00000589042.5
TTN-AS1NR_038272.1 linkuse as main transcriptn.2043+4293C>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TTNENST00000589042.5 linkuse as main transcriptc.94774G>C p.Val31592Leu missense_variant 341/3635 NM_001267550.2 P1
TTN-AS1ENST00000659121.1 linkuse as main transcriptn.416+23018C>G intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Benign
-0.072
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
18
DANN
Benign
0.87
Eigen
Uncertain
0.27
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.87
D;D;D;.;D;D;D
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.31
T;T;T;T;T;T;T
MetaSVM
Benign
-0.71
T
MutationAssessor
Benign
1.2
.;.;.;L;.;.;L
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-1.9
N;N;.;.;N;N;.
REVEL
Benign
0.12
Sift
Benign
0.038
D;D;.;.;D;D;.
Polyphen
0.60
.;.;.;P;.;.;P
Vest4
0.43
MutPred
0.37
.;.;.;Loss of catalytic residue at V29951 (P = 0.062);.;.;Loss of catalytic residue at V29951 (P = 0.062);
MVP
0.57
MPC
0.24
ClinPred
0.59
D
GERP RS
5.2

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: rs370918800; hg19: chr2-179411381; API