2-178698916-TAAAAAAAAAA-TAAAAAAA

Variant names:

• chr2-178698916-TAAA-T
• rs368277751
• NM_001267550.2:c.30683-5_30683-3delTTT

Variant summary

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

The NM_001267550.2(TTN):​c.30683-5_30683-3delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000833 in 1,218,420 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00083 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.01
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.30683-5_30683-3delTTT		splice_region_variant, intron_variant	Intron 111 of 362	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.30683-5_30683-3delTTT		splice_region_variant, intron_variant	Intron 111 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 85092 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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00410 AC: 270 AN: 65808 AF XY: 0.00408

Gnomad AFR exome AF: 0.00279

Gnomad AMR exome AF: 0.00839

Gnomad ASJ exome AF: 0.00373

Gnomad EAS exome AF: 0.00479

Gnomad FIN exome AF: 0.00453

Gnomad NFE exome AF: 0.00352

Gnomad OTH exome AF: 0.00396

GnomAD4 exome AF: 0.000833 AC: 1015 AN: 1218420 Hom.: 0 AF XY: 0.000887 AC XY: 533 AN XY: 600976

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

African (AFR) AF: 0.000815 AC: 21 AN: 25758

American (AMR) AF: 0.00330 AC: 67 AN: 20288

Ashkenazi Jewish (ASJ) AF: 0.00152 AC: 32 AN: 21122

East Asian (EAS) AF: 0.00109 AC: 35 AN: 32248

South Asian (SAS) AF: 0.00195 AC: 117 AN: 60068

European-Finnish (FIN) AF: 0.00168 AC: 55 AN: 32834

Middle Eastern (MID) AF: 0.000489 AC: 2 AN: 4094

European-Non Finnish (NFE) AF: 0.000657 AC: 638 AN: 971304

Other (OTH) AF: 0.000947 AC: 48 AN: 50704

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 85092 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 40596

African (AFR) AF: 0.00 AC: 0 AN: 21538

American (AMR) AF: 0.00 AC: 0 AN: 7934

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2106

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: 4376

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 41390

Other (OTH) AF: 0.00 AC: 0 AN: 1068

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 20, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs368277751; hg19: chr2-179563643;