2-178647040-GTATATATATA-GTATATATATATATATATATATATA

Position:

• chr2-178647040-GTATATATATA-GTATATATATATATATATATATATA

Variant summary

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

The NM_001267550.2(TTN):​c.40222+23_40222+24insTATATATATATATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00026 in 731,420 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 21)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.212

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]

LOC124906100 (HGNC:):

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.40222+23_40222+24insTATATATATATATA		intron_variant		ENST00000589042.5	NP_001254479.2
LOC124906100	XR_007087318.1	n.2185+2548_2185+2561dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.40222+23_40222+24insTATATATATATATA		intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.502+49368_502+49381dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 148 AN: 143268 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.000126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000419

Gnomad ASJ AF: 0.000593

Gnomad EAS AF: 0.000614

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000693

Gnomad MID AF: 0.00340

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.00103

GnomAD4 exome AF: 0.0000714 AC: 42 AN: 588086 Hom.: 0 Cov.: 0 AF XY: 0.0000581 AC XY: 17 AN XY: 292394

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000518

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000178

Gnomad4 NFE exome AF: 0.0000739

Gnomad4 OTH exome AF: 0.0000397

GnomAD4 genome AF: 0.00103 AC: 148 AN: 143334 Hom.: 0 Cov.: 21 AF XY: 0.000891 AC XY: 62 AN XY: 69546

Gnomad4 AFR AF: 0.000126

Gnomad4 AMR AF: 0.000419

Gnomad4 ASJ AF: 0.000593

Gnomad4 EAS AF: 0.000616

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000693

Gnomad4 NFE AF: 0.00190

Gnomad4 OTH AF: 0.00102

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10580462; hg19: chr2-179511767;