NM_001267550.2:c.30683-6_30683-3delTTTT

Variant names:

• chr2-178698916-TAAAA-T
• rs368277751
• NM_001267550.2:c.30683-6_30683-3delTTTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001267550.2(TTN):​c.30683-6_30683-3delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000054 in 1,313,990 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000012 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000057 (0 hom.)
• Consequence: TTN NM_001267550.2 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B: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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 2-178698916-TAAAA-T is Benign according to our data. Variant chr2-178698916-TAAAA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 282616.Status of the report is criteria_provided_single_submitter, 1 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.30683-6_30683-3delTTTT		splice_region intron	N/A	NP_001254479.2
	TTN	NM_001256850.1		c.29732-6_29732-3delTTTT		splice_region intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.26951-6_26951-3delTTTT		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.30683-6_30683-3delTTTT		splice_region intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.30683-6_30683-3delTTTT		splice_region intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.30407-6_30407-3delTTTT		splice_region intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000117 AC: 1 AN: 85112 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: 0.000323

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

GnomAD4 exome AF: 0.0000570 AC: 70 AN: 1228878 Hom.: 0 AF XY: 0.0000610 AC XY: 37 AN XY: 606250

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

African (AFR) AF: 0.000192 AC: 5 AN: 26022

American (AMR) AF: 0.000341 AC: 7 AN: 20522

Ashkenazi Jewish (ASJ) AF: 0.0000468 AC: 1 AN: 21360

East Asian (EAS) AF: 0.0000614 AC: 2 AN: 32562

South Asian (SAS) AF: 0.000132 AC: 8 AN: 60816

European-Finnish (FIN) AF: 0.000121 AC: 4 AN: 33152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.0000378 AC: 37 AN: 979140

Other (OTH) AF: 0.000117 AC: 6 AN: 51176

⚠️ 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: 0.0000117 AC: 1 AN: 85112 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 40612

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

American (AMR) AF: 0.00 AC: 0 AN: 7932

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

East Asian (EAS) AF: 0.000323 AC: 1 AN: 3094

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4380

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 41402

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 11, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0

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; COSMIC: COSV59910017; COSMIC: COSV59910017;