NM_001267550.2:c.27896T>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001267550.2(TTN):​c.27896T>G​(p.Leu9299Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000996 in 1,605,780 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

6
10

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.86

Publications

0 publications found
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 was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.31351286).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.27896T>G p.Leu9299Arg missense_variant Exon 97 of 363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.27896T>G p.Leu9299Arg missense_variant Exon 97 of 363 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152230
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00
GnomAD2 exomes
AF:
0.00000410
AC:
1
AN:
244142
AF XY:
0.00000756
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000901
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1453550
Hom.:
0
Cov.:
31
AF XY:
0.0000125
AC XY:
9
AN XY:
722040
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33104
American (AMR)
AF:
0.0000228
AC:
1
AN:
43954
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25828
East Asian (EAS)
AF:
0.0000253
AC:
1
AN:
39584
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85016
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53222
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5728
European-Non Finnish (NFE)
AF:
0.0000108
AC:
12
AN:
1107090
Other (OTH)
AF:
0.0000167
AC:
1
AN:
60024
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.482
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152230
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74368
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41464
American (AMR)
AF:
0.0000654
AC:
1
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5200
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68042
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000329
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Aug 11, 2016
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Uncertain:1
Oct 25, 2017
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.080
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
22
DANN
Benign
0.88
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.64
T;T;.;T
M_CAP
Benign
0.026
D
MetaRNN
Benign
0.31
T;T;T;T
MetaSVM
Benign
-0.94
T
PhyloP100
6.9
PrimateAI
Uncertain
0.59
T
PROVEAN
Uncertain
-3.4
D;.;.;.
REVEL
Benign
0.096
Sift
Uncertain
0.021
D;.;.;.
Polyphen
0.80
.;.;P;P
Vest4
0.57
MVP
0.56
MPC
0.25
ClinPred
0.31
T
GERP RS
5.6
Mutation Taster
=75/25
polymorphism

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

Other links and lift over

dbSNP: rs879046044; hg19: chr2-179576067; COSMIC: COSV60195411; API