2-178698916-TAAAAAAAAA-TAAAAAAAAAAAAAAAAAAA

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001267550.2(TTN):c.30683-3_30683-2insTTTTTTTTTT variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.401

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP6: Variant 2-178698916-T-TAAAAAAAAAA is Benign according to our data. Variant chr2-178698916-T-TAAAAAAAAAA is described in ClinVar as [Likely_benign]. Clinvar id is 437096.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.30683-3_30683-2insTTTTTTTTTT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000589042.5
LOC124906100	XR_007087318.1	n.2186-14832_2186-14823dup		intron_variant, non_coding_transcript_variant
LOC124907912	XR_007087321.1	n.7314+3471_7314+3480dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.30683-3_30683-2insTTTTTTTTTT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.503-35582_503-35573dup		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes AF: 0.00129 AC: 85 AN: 65808 Hom.: 0 AF XY: 0.00112 AC XY: 40 AN XY: 35820

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 SAS exome AF: 0.000285

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

Gnomad4 AFR exome AF: 0.000691

Gnomad4 AMR exome AF: 0.000973

Gnomad4 ASJ exome AF: 0.000328

Gnomad4 EAS exome AF: 0.00157

Gnomad4 SAS exome AF: 0.00105

Gnomad4 FIN exome AF: 0.000271

Gnomad4 NFE exome AF: 0.000201

Gnomad4 OTH exome AF: 0.000391

GnomAD4 genome AF: 0.0000353 AC: 3 AN: 84920 Hom.: 0 Cov.: 30 AF XY: 0.0000493 AC XY: 2 AN XY: 40538

Gnomad4 AFR AF: 0.000139

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 02, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs368277751; hg19: chr2-179563643;