2-178647040-GTATATATATA-GTATATATATATATATATATATATATATATATATA

Variant names:

• chr2-178647040-G-GTATATATATATATATATATATATA
• rs10580462
• NM_001267550.2:c.40222+23_40222+24insTATATATATATATATATATATATA

Variant summary

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

The NM_001267550.2(TTN):​c.40222+23_40222+24insTATATATATATATATATATATATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 143,340 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 0.00011 (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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. 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.40222+23_40222+24insTATATATATATATATATATATATA		intron	N/A	NP_001254479.2
	TTN	NM_001256850.1		c.35375-1011_35375-1010insTATATATATATATATATATATATA		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.32594-1011_32594-1010insTATATATATATATATATATATATA		intron	N/A	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.40222+23_40222+24insTATATATATATATATATATATATA		intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.40222+23_40222+24insTATATATATATATATATATATATA		intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.39946+23_39946+24insTATATATATATATATATATATATA		intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 16 AN: 143274 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000757

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00112

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000771

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: 0.000112 AC: 16 AN: 143340 Hom.: 0 Cov.: 21 AF XY: 0.000115 AC XY: 8 AN XY: 69546

African (AFR) AF: 0.0000755 AC: 3 AN: 39728

American (AMR) AF: 0.000209 AC: 3 AN: 14326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3372

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

South Asian (SAS) AF: 0.00113 AC: 5 AN: 4442

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: 0.0000771 AC: 5 AN: 64838

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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;