2-178698916-TAAAAAAAAAA-TAAAAAAAA

Variant names:

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

Variant summary

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

The NM_001267550.2(TTN):​c.30683-4_30683-3delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,239,238 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 0.00032 (0 hom., cov: 30)
  • Exomes 𝑓: 0.013 (0 hom.)
• Consequence: TTN NM_001267550.2 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.954
• 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-TAA-T is Benign according to our data. Variant chr2-178698916-TAA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 695340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.30683-4_30683-3delTT		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.30683-4_30683-3delTT		splice_region_variant, intron_variant	Intron 111 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.000317 AC: 27 AN: 85050 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000378

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000363

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0344 AC: 2265 AN: 65808 AF XY: 0.0339

Gnomad AFR exome AF: 0.0340

Gnomad AMR exome AF: 0.0481

Gnomad ASJ exome AF: 0.0301

Gnomad EAS exome AF: 0.0420

Gnomad FIN exome AF: 0.0340

Gnomad NFE exome AF: 0.0293

Gnomad OTH exome AF: 0.0311

GnomAD4 exome AF: 0.0128 AC: 14750 AN: 1154170 Hom.: 0 AF XY: 0.0132 AC XY: 7520 AN XY: 569540

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

African (AFR) AF: 0.0144 AC: 352 AN: 24374

American (AMR) AF: 0.0322 AC: 622 AN: 19314

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 353 AN: 20028

East Asian (EAS) AF: 0.0164 AC: 496 AN: 30246

South Asian (SAS) AF: 0.0271 AC: 1547 AN: 57066

European-Finnish (FIN) AF: 0.0191 AC: 591 AN: 30914

Middle Eastern (MID) AF: 0.0139 AC: 54 AN: 3890

European-Non Finnish (NFE) AF: 0.0110 AC: 10082 AN: 920358

Other (OTH) AF: 0.0136 AC: 653 AN: 47980

⚠️ 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: 0.000317 AC: 27 AN: 85068 Hom.: 0 Cov.: 30 AF XY: 0.000443 AC XY: 18 AN XY: 40598

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

African (AFR) AF: 0.000185 AC: 4 AN: 21578

American (AMR) AF: 0.000378 AC: 3 AN: 7944

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3076

South Asian (SAS) AF: 0.00 AC: 0 AN: 2898

European-Finnish (FIN) AF: 0.00114 AC: 5 AN: 4372

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

European-Non Finnish (NFE) AF: 0.000363 AC: 15 AN: 41350

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.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy Benign:1

Sep 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jul 25, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.95
Mutation Taster		=91/9	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; COSMIC: COSV60018477; COSMIC: COSV60018477;