2-178526912-C-CT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_001267550.2(TTN):​c.*99_*100insA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 11668 hom., cov: 0)
Exomes 𝑓: 0.26 ( 40006 hom. )

Consequence

TTN
NM_001267550.2 3_prime_UTR

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.858
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 Benign. Variant got -16 ACMG points.

BP6
Variant 2-178526912-C-CT is Benign according to our data. Variant chr2-178526912-C-CT is described in ClinVar as [Likely_benign]. Clinvar id is 332674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.681 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TTNNM_001267550.2 linkuse as main transcriptc.*99_*100insA 3_prime_UTR_variant 363/363 ENST00000589042.5 NP_001254479.2
TTN-AS1NR_038272.1 linkuse as main transcriptn.219+3284dup intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkuse as main transcriptc.*99_*100insA 3_prime_UTR_variant 363/3635 NM_001267550.2 ENSP00000467141 P1
TTN-AS1ENST00000659121.1 linkuse as main transcriptn.416+3284dup intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.360
AC:
54601
AN:
151822
Hom.:
11619
Cov.:
0
show subpopulations
Gnomad AFR
AF:
0.534
Gnomad AMI
AF:
0.560
Gnomad AMR
AF:
0.384
Gnomad ASJ
AF:
0.285
Gnomad EAS
AF:
0.700
Gnomad SAS
AF:
0.515
Gnomad FIN
AF:
0.285
Gnomad MID
AF:
0.278
Gnomad NFE
AF:
0.225
Gnomad OTH
AF:
0.327
GnomAD4 exome
AF:
0.256
AC:
262040
AN:
1024052
Hom.:
40006
Cov.:
13
AF XY:
0.260
AC XY:
130352
AN XY:
501178
show subpopulations
Gnomad4 AFR exome
AF:
0.538
Gnomad4 AMR exome
AF:
0.404
Gnomad4 ASJ exome
AF:
0.273
Gnomad4 EAS exome
AF:
0.685
Gnomad4 SAS exome
AF:
0.487
Gnomad4 FIN exome
AF:
0.270
Gnomad4 NFE exome
AF:
0.211
Gnomad4 OTH exome
AF:
0.293
GnomAD4 genome
AF:
0.360
AC:
54712
AN:
151940
Hom.:
11668
Cov.:
0
AF XY:
0.370
AC XY:
27468
AN XY:
74252
show subpopulations
Gnomad4 AFR
AF:
0.535
Gnomad4 AMR
AF:
0.384
Gnomad4 ASJ
AF:
0.285
Gnomad4 EAS
AF:
0.700
Gnomad4 SAS
AF:
0.514
Gnomad4 FIN
AF:
0.285
Gnomad4 NFE
AF:
0.225
Gnomad4 OTH
AF:
0.335
Bravo
AF:
0.377

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Early-onset myopathy with fatal cardiomyopathy Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 10, 2021- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Tibial muscular dystrophy Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 10, 2021- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Myopathy, myofibrillar, 9, with early respiratory failure Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 10, 2021- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 10, 2021- -
Limb-girdle muscular dystrophy, recessive Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Dilated Cardiomyopathy, Dominant Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxAug 18, 2019- -
Hypertrophic cardiomyopathy Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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: rs11424072; hg19: chr2-179391639; API