2-178525940-A-G

Variant summary

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

The NR_038272.1(TTN-AS1):​n.219+2304A>G variant causes a intron, non coding transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 152,470 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 70 hom., cov: 33)
Exomes 𝑓: 0.035 ( 0 hom. )

Consequence

TTN-AS1
NR_038272.1 intron, non_coding_transcript

Scores

2

Clinical Significance

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

Conservation

PhyloP100: -0.168
Variant links:
Genes affected
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.96).
BP6
Variant 2-178525940-A-G is Benign according to our data. Variant chr2-178525940-A-G is described in ClinVar as [Benign]. Clinvar id is 1262402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0586 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TTN-AS1NR_038272.1 linkuse as main transcriptn.219+2304A>G intron_variant, non_coding_transcript_variant
TTNNM_001267550.2 linkuse as main transcript downstream_gene_variant ENST00000589042.5 NP_001254479.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TTN-AS1ENST00000659121.1 linkuse as main transcriptn.416+2304A>G intron_variant, non_coding_transcript_variant
TTNENST00000589042.5 linkuse as main transcript downstream_gene_variant 5 NM_001267550.2 ENSP00000467141 P1

Frequencies

GnomAD3 genomes
AF:
0.0235
AC:
3570
AN:
152152
Hom.:
69
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00485
Gnomad AMI
AF:
0.0307
Gnomad AMR
AF:
0.0237
Gnomad ASJ
AF:
0.0204
Gnomad EAS
AF:
0.0639
Gnomad SAS
AF:
0.0323
Gnomad FIN
AF:
0.0617
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.0253
Gnomad OTH
AF:
0.0215
GnomAD4 exome
AF:
0.0350
AC:
7
AN:
200
Hom.:
0
Cov.:
0
AF XY:
0.0234
AC XY:
3
AN XY:
128
show subpopulations
Gnomad4 FIN exome
AF:
0.0372
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0235
AC:
3572
AN:
152270
Hom.:
70
Cov.:
33
AF XY:
0.0251
AC XY:
1868
AN XY:
74454
show subpopulations
Gnomad4 AFR
AF:
0.00484
Gnomad4 AMR
AF:
0.0237
Gnomad4 ASJ
AF:
0.0204
Gnomad4 EAS
AF:
0.0642
Gnomad4 SAS
AF:
0.0326
Gnomad4 FIN
AF:
0.0617
Gnomad4 NFE
AF:
0.0253
Gnomad4 OTH
AF:
0.0213
Alfa
AF:
0.0217
Hom.:
4
Bravo
AF:
0.0201
Asia WGS
AF:
0.0430
AC:
150
AN:
3478

ClinVar

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

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxMay 19, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.96
CADD
Benign
1.5
DANN
Benign
0.33

Splicing

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: rs72629800; hg19: chr2-179390667; API