2-178698916-TAAAAAAAAAA-TAAAAAAAAAAAA

Variant names:

• chr2-178698916-T-TAA
• rs368277751
• NM_001267550.2:c.30683-4_30683-3dupTT

Variant summary

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

The NM_001267550.2(TTN):​c.30683-4_30683-3dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,311,622 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 0.000047 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: TTN NM_001267550.2 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.401
• Publications: 3 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.30683-4_30683-3dupTT		splice_region intron	N/A	NP_001254479.2
	TTN	NM_001256850.1		c.29732-4_29732-3dupTT		splice_region intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.26951-4_26951-3dupTT		splice_region 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.30683-3_30683-2insTT		splice_region intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.30683-3_30683-2insTT		splice_region intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.30407-3_30407-2insTT		splice_region intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000470 AC: 4 AN: 85116 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000966

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00281 AC: 185 AN: 65808 AF XY: 0.00296

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00341

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.00160

Gnomad FIN exome AF: 0.000252

Gnomad NFE exome AF: 0.00372

Gnomad OTH exome AF: 0.00339

GnomAD4 exome AF: 0.00119 AC: 1461 AN: 1226506 Hom.: 0 Cov.: 0 AF XY: 0.00122 AC XY: 736 AN XY: 605146

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

African (AFR) AF: 0.000885 AC: 23 AN: 25976

American (AMR) AF: 0.00214 AC: 44 AN: 20534

Ashkenazi Jewish (ASJ) AF: 0.00155 AC: 33 AN: 21330

East Asian (EAS) AF: 0.000431 AC: 14 AN: 32518

South Asian (SAS) AF: 0.00156 AC: 95 AN: 60714

European-Finnish (FIN) AF: 0.00121 AC: 40 AN: 33134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4112

European-Non Finnish (NFE) AF: 0.00120 AC: 1168 AN: 977100

Other (OTH) AF: 0.000861 AC: 44 AN: 51088

⚠️ 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: 0.0000470 AC: 4 AN: 85116 Hom.: 0 Cov.: 30 AF XY: 0.0000739 AC XY: 3 AN XY: 40614

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

African (AFR) AF: 0.00 AC: 0 AN: 21534

American (AMR) AF: 0.00 AC: 0 AN: 7936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2110

East Asian (EAS) AF: 0.00 AC: 0 AN: 3094

South Asian (SAS) AF: 0.00 AC: 0 AN: 2912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 152

European-Non Finnish (NFE) AF: 0.0000966 AC: 4 AN: 41402

Other (OTH) AF: 0.00 AC: 0 AN: 1070

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0249301), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.40

Splicing

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

Other links and lift over

dbSNP: rs368277751; hg19: chr2-179563643;