chr2-178662773-G-A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001267550.2(TTN):​c.36830C>T​(p.Ala12277Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 20)
Exomes 𝑓: 0.000084 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

TTN
NM_001267550.2 missense

Scores

11

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.638

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 -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.015921652).
BP6
Variant 2-178662773-G-A is Benign according to our data. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.36830C>T p.Ala12277Val missense_variant Exon 175 of 363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.36830C>T p.Ala12277Val missense_variant Exon 175 of 363 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.000119
AC:
16
AN:
134780
Hom.:
0
Cov.:
20
show subpopulations
Gnomad AFR
AF:
0.000282
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000152
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:
0.0000636
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000519
AC:
29
AN:
55920
AF XY:
0.000713
show subpopulations
Gnomad AFR exome
AF:
0.000568
Gnomad AMR exome
AF:
0.000557
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000127
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000138
Gnomad OTH exome
AF:
0.00103
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.0000837
AC:
102
AN:
1218788
Hom.:
0
Cov.:
17
AF XY:
0.000103
AC XY:
63
AN XY:
609500
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.000252
AC:
7
AN:
27820
American (AMR)
AF:
0.000166
AC:
6
AN:
36136
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
21694
East Asian (EAS)
AF:
0.0000267
AC:
1
AN:
37466
South Asian (SAS)
AF:
0.000775
AC:
58
AN:
74812
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
39490
Middle Eastern (MID)
AF:
0.000853
AC:
3
AN:
3516
European-Non Finnish (NFE)
AF:
0.0000248
AC:
23
AN:
926268
Other (OTH)
AF:
0.0000775
AC:
4
AN:
51586
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.342
Heterozygous variant carriers
0
6
11
17
22
28
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
Data not reliable, filtered out with message: AS_VQSR
AF:
0.000119
AC:
16
AN:
134866
Hom.:
0
Cov.:
20
AF XY:
0.0000927
AC XY:
6
AN XY:
64702
show subpopulations
African (AFR)
AF:
0.000281
AC:
10
AN:
35590
American (AMR)
AF:
0.000152
AC:
2
AN:
13194
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3250
East Asian (EAS)
AF:
0.00
AC:
0
AN:
4480
South Asian (SAS)
AF:
0.00
AC:
0
AN:
3814
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
8744
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
280
European-Non Finnish (NFE)
AF:
0.0000636
AC:
4
AN:
62898
Other (OTH)
AF:
0.00
AC:
0
AN:
1768
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.416
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

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

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Apr 29, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
5.6
DANN
Benign
0.72
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.00091
N
LIST_S2
Benign
0.21
T
M_CAP
Benign
0.026
D
MetaRNN
Benign
0.016
T
MetaSVM
Benign
-1.0
T
PhyloP100
-0.64
Vest4
0.030
MVP
0.25
MPC
0.083
ClinPred
0.0058
T
GERP RS
3.3
Mutation Taster
=93/7
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs878854300; hg19: chr2-179527500; API