rs2046778

Positions:

• chr2-178807820-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The ENST00000412264.1(TTN):​c.-13-3165A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 151,766 control chromosomes in the GnomAD database, including 5,078 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.25 (5078 hom., cov: 31)
• Consequence: TTN ENST00000412264.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.66

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000412264.1	c.-13-3165A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37625 AN: 151648 Hom.: 5071 Cov.: 31

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.336

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.295

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.248 AC: 37665 AN: 151766 Hom.: 5078 Cov.: 31 AF XY: 0.240 AC XY: 17783 AN XY: 74176

Gnomad4 AFR AF: 0.321

Gnomad4 AMR AF: 0.217

Gnomad4 ASJ AF: 0.336

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.125

Gnomad4 FIN AF: 0.143

Gnomad4 NFE AF: 0.242

Gnomad4 OTH AF: 0.292

Alfa AF: 0.237 Hom.: 2101

Bravo AF: 0.261

Asia WGS AF: 0.143 AC: 498 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Benign	0.92

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2046778; hg19: chr2-179672547;