chr2-178752043-GAAAAA-G

Variant names:

• chr2-178752043-GAAAAA-G
• rs58651353
• NM_001267550.2:c.11311+1076_11311+1080delTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_133379.5(TTN):​c.10361-9_10361-5delTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_133379.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.55
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133379.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.11311+1076_11311+1080delTTTTT		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.10360+1076_10360+1080delTTTTT		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.10360+1076_10360+1080delTTTTT		intron	N/A	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.11311+1076_11311+1080delTTTTT		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.11311+1076_11311+1080delTTTTT		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.11035+1076_11035+1080delTTTTT		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1258584 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 630120

African (AFR) AF: 0.00 AC: 0 AN: 26398

American (AMR) AF: 0.00 AC: 0 AN: 32266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22986

East Asian (EAS) AF: 0.00 AC: 0 AN: 34802

South Asian (SAS) AF: 0.00 AC: 0 AN: 72494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4998

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 967842

Other (OTH) AF: 0.00 AC: 0 AN: 52350

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs58651353; hg19: chr2-179616770;