2-178614019-CTTTTT-CTTTT

Variant names:

• chr2-178614019-CT-C
• rs566373563
• NM_001267550.2:c.49345+32delA

Variant summary

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

The NM_001267550.2(TTN):​c.49345+32delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000555 in 1,439,350 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 0.000054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (0 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0760
• Publications: 0 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]

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.49345+32delA		intron	N/A	NP_001254479.2
	TTN	NM_001256850.1		c.44422+32delA		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.41641+32delA		intron	N/A	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.49345+32delA		intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.49189+32delA		intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.49069+32delA		intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000538 AC: 8 AN: 148612 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000986

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000999

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000449

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00612 AC: 904 AN: 147624 AF XY: 0.00626

Gnomad AFR exome AF: 0.00316

Gnomad AMR exome AF: 0.00888

Gnomad ASJ exome AF: 0.00618

Gnomad EAS exome AF: 0.00672

Gnomad FIN exome AF: 0.00163

Gnomad NFE exome AF: 0.00622

Gnomad OTH exome AF: 0.00854

GnomAD4 exome AF: 0.000613 AC: 791 AN: 1290636 Hom.: 0 Cov.: 34 AF XY: 0.000678 AC XY: 436 AN XY: 643064

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

African (AFR) AF: 0.00152 AC: 44 AN: 28902

American (AMR) AF: 0.00429 AC: 160 AN: 37330

Ashkenazi Jewish (ASJ) AF: 0.000872 AC: 20 AN: 22946

East Asian (EAS) AF: 0.000370 AC: 13 AN: 35156

South Asian (SAS) AF: 0.00182 AC: 137 AN: 75110

European-Finnish (FIN) AF: 0.000394 AC: 19 AN: 48250

Middle Eastern (MID) AF: 0.000757 AC: 4 AN: 5286

European-Non Finnish (NFE) AF: 0.000375 AC: 369 AN: 984396

Other (OTH) AF: 0.000469 AC: 25 AN: 53260

⚠️ 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: 0.0000538 AC: 8 AN: 148714 Hom.: 0 Cov.: 32 AF XY: 0.0000552 AC XY: 4 AN XY: 72482

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

African (AFR) AF: 0.0000984 AC: 4 AN: 40662

American (AMR) AF: 0.00 AC: 0 AN: 14930

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3398

East Asian (EAS) AF: 0.00 AC: 0 AN: 5052

South Asian (SAS) AF: 0.00 AC: 0 AN: 4676

European-Finnish (FIN) AF: 0.0000999 AC: 1 AN: 10006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000450 AC: 3 AN: 66734

Other (OTH) AF: 0.00 AC: 0 AN: 2054

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000187107), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0147 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.076
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs566373563; hg19: chr2-179478746; COSMIC: COSV60184182; COSMIC: COSV60184182;