rs58651353

Positions:

• chr2-178752043-GAAAA-G
• chr2-178752043-GAAAA-GA
• chr2-178752043-GAAAA-GAA
• chr2-178752043-GAAAA-GAAA
• chr2-178752043-GAAAA-GAAAAA
• chr2-178752043-GAAAA-GAAAAAA
• chr2-178752043-GAAAA-GAAAAAAA
• chr2-178752043-GAAAA-GAAAAAAAAA
• chr2-178752043-GAAAA-GAAAAAAAAAAAA
• chr2-178752043-GAAAA-GAAAAAAAAAAAAAA
• chr2-178752043-GAAAA-GAAAAAAAAAAAAAAAAA
• chr2-178752043-GAAAA-GAAAAAAAAAAAAAAAATTTATAATTTTTCATAAAAAATAAAAAAAAAAA

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_133379.5(TTN):​c.10361-8_10361-5del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000556 in 1,258,426 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: TTN NM_133379.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.55

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.11311+1077_11311+1080del		intron_variant		ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.10361-8_10361-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000360870.10	NP_596870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000360870.10	c.10361-8_10361-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_133379.5	ENSP00000354117
TTN	ENST00000589042.5	c.11311+1077_11311+1080del		intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.1224-4211_1224-4208del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000556 AC: 7 AN: 1258426 Hom.: 0 AF XY: 0.00000317 AC XY: 2 AN XY: 630046

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000310

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000900

Gnomad4 NFE exome AF: 0.00000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs58651353; hg19: chr2-179616770;