2-178647040-GTATATATATA-GTATATATATATATATATATATATA

Variant names:

• chr2-178647040-G-GTATATATATATATA
• rs10580462
• NM_001267550.2:c.40222+10_40222+23dupTATATATATATATA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001267550.2(TTN):​c.40222+10_40222+23dupTATATATATATATA 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. 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 0.0010 (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
• 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00103 (148/143334) while in subpopulation NFE AF = 0.0019 (123/64834). AF 95% confidence interval is 0.00162. There are 0 homozygotes in GnomAd4. There are 62 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.40222+10_40222+23dupTATATATATATATA		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+24insTATATATATATATA		intron_variant	Intron 215 of 362	5	NM_001267550.2	ENSP00000467141.1

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

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

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: 0.0000518 AC: 1 AN: 19322

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

European-Finnish (FIN) AF: 0.000178 AC: 5 AN: 28092

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

European-Non Finnish (NFE) AF: 0.0000739 AC: 35 AN: 473384

Other (OTH) AF: 0.0000397 AC: 1 AN: 25180

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.000126 AC: 5 AN: 39724

American (AMR) AF: 0.000419 AC: 6 AN: 14326

Ashkenazi Jewish (ASJ) AF: 0.000593 AC: 2 AN: 3374

East Asian (EAS) AF: 0.000616 AC: 3 AN: 4870

South Asian (SAS) AF: 0.00 AC: 0 AN: 4444

European-Finnish (FIN) AF: 0.000693 AC: 6 AN: 8654

Middle Eastern (MID) AF: 0.00370 AC: 1 AN: 270

European-Non Finnish (NFE) AF: 0.00190 AC: 123 AN: 64834

Other (OTH) AF: 0.00102 AC: 2 AN: 1958

Alfa AF: 0.000492 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;