2-178614019-CT-CTT

Position:

• chr2-178614019-CT-CTT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001267550.2(TTN):​c.49345+32dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,440,954 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (3 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0760

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:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 2-178614019-C-CT is Benign according to our data. Variant chr2-178614019-C-CT is described in ClinVar as [Likely_benign]. Clinvar id is 445299.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00123 (183/148748) while in subpopulation SAS AF= 0.0124 (58/4676). AF 95% confidence interval is 0.00985. There are 0 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.49345+32dupA		intron_variant		ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.49345+32dupA		intron_variant		5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 183 AN: 148646 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000345

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00181

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000987

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.000200

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00196

GnomAD4 exome AF: 0.00205 AC: 2646 AN: 1292206 Hom.: 3 Cov.: 34 AF XY: 0.00236 AC XY: 1522 AN XY: 644264

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.00279

Gnomad4 ASJ exome AF: 0.000951

Gnomad4 EAS exome AF: 0.000706

Gnomad4 SAS exome AF: 0.0147

Gnomad4 FIN exome AF: 0.000391

Gnomad4 NFE exome AF: 0.00122

Gnomad4 OTH exome AF: 0.00198

GnomAD4 genome AF: 0.00123 AC: 183 AN: 148748 Hom.: 0 Cov.: 32 AF XY: 0.00139 AC XY: 101 AN XY: 72498

Gnomad4 AFR AF: 0.000344

Gnomad4 AMR AF: 0.00181

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000990

Gnomad4 SAS AF: 0.0124

Gnomad4 FIN AF: 0.000200

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.00195

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jun 05, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs566373563; hg19: chr2-179478746;