2-178774570-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001267550.2(TTN):​c.6791-97G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.971 in 1,162,060 control chromosomes in the GnomAD database, including 549,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.93 ( 66197 hom., cov: 32)
Exomes 𝑓: 0.98 ( 482920 hom. )

Consequence

TTN
NM_001267550.2 intron

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.466
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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
Variant 2-178774570-C-T is Benign according to our data. Variant chr2-178774570-C-T is described in ClinVar as [Benign]. Clinvar id is 1275365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.6791-97G>A intron_variant Intron 29 of 362 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7
TTNNM_133379.5 linkc.6791-97G>A intron_variant Intron 29 of 45 ENST00000360870.10 NP_596870.2 Q8WZ42-6Q7Z3B7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.6791-97G>A intron_variant Intron 29 of 362 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7
TTNENST00000360870.10 linkc.6791-97G>A intron_variant Intron 29 of 45 5 NM_133379.5 ENSP00000354117.4 Q8WZ42-6

Frequencies

GnomAD3 genomes
AF:
0.929
AC:
141325
AN:
152130
Hom.:
66170
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.803
Gnomad AMI
AF:
0.843
Gnomad AMR
AF:
0.958
Gnomad ASJ
AF:
0.994
Gnomad EAS
AF:
0.874
Gnomad SAS
AF:
0.952
Gnomad FIN
AF:
0.980
Gnomad MID
AF:
0.978
Gnomad NFE
AF:
0.991
Gnomad OTH
AF:
0.936
GnomAD4 exome
AF:
0.977
AC:
986749
AN:
1009812
Hom.:
482920
Cov.:
13
AF XY:
0.978
AC XY:
504185
AN XY:
515790
show subpopulations
Gnomad4 AFR exome
AF:
0.794
Gnomad4 AMR exome
AF:
0.943
Gnomad4 ASJ exome
AF:
0.993
Gnomad4 EAS exome
AF:
0.869
Gnomad4 SAS exome
AF:
0.958
Gnomad4 FIN exome
AF:
0.977
Gnomad4 NFE exome
AF:
0.992
Gnomad4 OTH exome
AF:
0.966
GnomAD4 genome
AF:
0.929
AC:
141402
AN:
152248
Hom.:
66197
Cov.:
32
AF XY:
0.930
AC XY:
69189
AN XY:
74436
show subpopulations
Gnomad4 AFR
AF:
0.802
Gnomad4 AMR
AF:
0.958
Gnomad4 ASJ
AF:
0.994
Gnomad4 EAS
AF:
0.874
Gnomad4 SAS
AF:
0.951
Gnomad4 FIN
AF:
0.980
Gnomad4 NFE
AF:
0.991
Gnomad4 OTH
AF:
0.937
Alfa
AF:
0.978
Hom.:
67636
Bravo
AF:
0.918
Asia WGS
AF:
0.903
AC:
3137
AN:
3474

ClinVar

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

Submissions by phenotype

not provided Benign:2
Jun 26, 2018
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.79
CADD
Benign
0.42
DANN
Benign
0.55

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: rs3816781; hg19: chr2-179639297; API