chr2-178622735-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001267550.2(TTN):​c.44848G>C​(p.Asp14950His) variant causes a missense change. The variant allele was found at a frequency of 0.00000125 in 1,605,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. D14950N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

6
5
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.18

Publications

3 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: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.41299444).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.44848G>C p.Asp14950His missense_variant Exon 243 of 363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.44848G>C p.Asp14950His missense_variant Exon 243 of 363 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.00000660
AC:
1
AN:
151578
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.88e-7
AC:
1
AN:
1453434
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
722304
show subpopulations
African (AFR)
AF:
0.0000301
AC:
1
AN:
33244
American (AMR)
AF:
0.00
AC:
0
AN:
43928
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25810
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39260
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84456
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53050
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5736
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1107976
Other (OTH)
AF:
0.00
AC:
0
AN:
59974
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
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:
0.00000660
AC:
1
AN:
151578
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
73992
show subpopulations
African (AFR)
AF:
0.0000242
AC:
1
AN:
41314
American (AMR)
AF:
0.00
AC:
0
AN:
15186
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5126
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4808
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10540
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67824
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.79
BayesDel_addAF
Benign
-0.022
T
BayesDel_noAF
Benign
-0.27
CADD
Uncertain
23
DANN
Benign
0.92
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.90
D;D;D;.;D;D;D
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.41
T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.22
T
MutationAssessor
Pathogenic
3.0
.;.;.;M;.;.;M
PhyloP100
7.2
PrimateAI
Uncertain
0.53
T
PROVEAN
Pathogenic
-5.4
D;D;.;.;D;D;.
REVEL
Uncertain
0.39
Sift
Uncertain
0.0030
D;D;.;.;D;D;.
Polyphen
1.0
.;.;.;D;.;.;D
Vest4
0.44
MVP
0.33
MPC
0.50
ClinPred
0.88
D
GERP RS
5.5
Mutation Taster
=58/42
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: rs571524382; hg19: chr2-179487462; API