NM_001267550.2:c.30683-12_30683-3dupTTTTTTTTTT

Variant names:

• chr2-178698916-T-TAAAAAAAAAA
• rs368277751
• NM_001267550.2:c.30683-12_30683-3dupTTTTTTTTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_001267550.2(TTN):​c.30683-12_30683-3dupTTTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000297 in 1,314,620 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000035 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: TTN NM_001267550.2 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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: Benign. The variant received -8 ACMG points.

• BP6: Variant 2-178698916-T-TAAAAAAAAAA is Benign according to our data. Variant chr2-178698916-T-TAAAAAAAAAA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 437096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.30683-12_30683-3dupTTTTTTTTTT		splice_region intron	N/A	NP_001254479.2
	TTN	NM_001256850.1		c.29732-12_29732-3dupTTTTTTTTTT		splice_region intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.26951-12_26951-3dupTTTTTTTTTT		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_30683-2insTTTTTTTTTT		splice_region intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.30683-3_30683-2insTTTTTTTTTT		splice_region intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.30407-3_30407-2insTTTTTTTTTT		splice_region intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000353 AC: 3 AN: 84900 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000140

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: 0.00129 AC: 85 AN: 65808 AF XY: 0.00112

Gnomad AFR exome AF: 0.00253

Gnomad AMR exome AF: 0.000787

Gnomad ASJ exome AF: 0.000746

Gnomad EAS exome AF: 0.00571

Gnomad FIN exome AF: 0.000503

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.000566

GnomAD4 exome AF: 0.000315 AC: 387 AN: 1229700 Hom.: 0 Cov.: 0 AF XY: 0.000359 AC XY: 218 AN XY: 606642

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

African (AFR) AF: 0.000691 AC: 18 AN: 26038

American (AMR) AF: 0.000973 AC: 20 AN: 20550

Ashkenazi Jewish (ASJ) AF: 0.000328 AC: 7 AN: 21370

East Asian (EAS) AF: 0.00157 AC: 51 AN: 32550

South Asian (SAS) AF: 0.00105 AC: 64 AN: 60822

European-Finnish (FIN) AF: 0.000271 AC: 9 AN: 33190

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4128

European-Non Finnish (NFE) AF: 0.000201 AC: 197 AN: 979868

Other (OTH) AF: 0.000391 AC: 20 AN: 51184

⚠️ 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: 0.0000353 AC: 3 AN: 84920 Hom.: 0 Cov.: 30 AF XY: 0.0000493 AC XY: 2 AN XY: 40538

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

African (AFR) AF: 0.000139 AC: 3 AN: 21534

American (AMR) AF: 0.00 AC: 0 AN: 7944

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3072

South Asian (SAS) AF: 0.00 AC: 0 AN: 2886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 142

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 41260

Other (OTH) AF: 0.00 AC: 0 AN: 1076

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:1

Sep 02, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTN-related myopathy Benign:1

Dec 13, 2018

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

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;