2-178647040-GTATATATATA-GTATATATATATATATATATATATATATATATA

Variant names:

• chr2-178647040-G-GTATATATATATATATATATATA
• rs10580462
• NM_001267550.2:c.40222+2_40222+23dupTATATATATATATATATATATA

Variant summary

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

The NM_001267550.2(TTN):​c.40222+2_40222+23dupTATATATATATATATATATATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000537 in 143,310 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 21)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.212
• Publications: 4 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]

LOC124906100 (HGNC:):

ACMG classification

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.40222+2_40222+23dupTATATATATATATATATATATA		intron_variant	Intron 215 of 362	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.40222+23_40222+24insTATATATATATATATATATATA		intron_variant	Intron 215 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.000538 AC: 77 AN: 143244 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000505

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000629

Gnomad ASJ AF: 0.000296

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000648

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 588112 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 292408

African (AFR) AF: 0.00 AC: 0 AN: 12696

American (AMR) AF: 0.00 AC: 0 AN: 7260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9790

East Asian (EAS) AF: 0.00 AC: 0 AN: 19322

South Asian (SAS) AF: 0.00 AC: 0 AN: 10496

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1866

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 473402

Other (OTH) AF: 0.00 AC: 0 AN: 25180

GnomAD4 genome AF: 0.000537 AC: 77 AN: 143310 Hom.: 0 Cov.: 21 AF XY: 0.000604 AC XY: 42 AN XY: 69532

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000503 AC: 2 AN: 39728

American (AMR) AF: 0.000629 AC: 9 AN: 14316

Ashkenazi Jewish (ASJ) AF: 0.000296 AC: 1 AN: 3374

East Asian (EAS) AF: 0.00 AC: 0 AN: 4870

South Asian (SAS) AF: 0.00519 AC: 23 AN: 4432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8656

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.000648 AC: 42 AN: 64826

Other (OTH) AF: 0.00 AC: 0 AN: 1958

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000703 Hom.: 16

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.21

Splicing

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

Other links and lift over

dbSNP: rs10580462; hg19: chr2-179511767;