rs2742327

Positions:

• chr2-178722960-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.21962-23A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,598,260 control chromosomes in the GnomAD database, including 62,956 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.34 (11036 hom., cov: 33)
  • Exomes 𝑓: 0.24 (51920 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.850

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 -20 ACMG points.

• BP4: This place is a probable branch point but rather VUS (scored 4 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-178722960-T-C is Benign according to our data. Variant chr2-178722960-T-C is described in ClinVar as [Benign]. Clinvar id is 671270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.21962-23A>G		intron_variant		ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.21962-23A>G		intron_variant		5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.343 AC: 52093 AN: 151876 Hom.: 10988 Cov.: 33

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.652

Gnomad SAS AF: 0.433

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.316

GnomAD3 exomes AF: 0.318 AC: 74865 AN: 235794 Hom.: 14816 AF XY: 0.310 AC XY: 39564 AN XY: 127778

Gnomad AFR exome AF: 0.558

Gnomad AMR exome AF: 0.419

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.670

Gnomad SAS exome AF: 0.429

Gnomad FIN exome AF: 0.203

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.245 AC: 354080 AN: 1446266 Hom.: 51920 Cov.: 35 AF XY: 0.247 AC XY: 177677 AN XY: 718002

Gnomad4 AFR exome AF: 0.567

Gnomad4 AMR exome AF: 0.416

Gnomad4 ASJ exome AF: 0.200

Gnomad4 EAS exome AF: 0.649

Gnomad4 SAS exome AF: 0.418

Gnomad4 FIN exome AF: 0.204

Gnomad4 NFE exome AF: 0.203

Gnomad4 OTH exome AF: 0.272

GnomAD4 genome AF: 0.343 AC: 52202 AN: 151994 Hom.: 11036 Cov.: 33 AF XY: 0.349 AC XY: 25936 AN XY: 74300

Gnomad4 AFR AF: 0.553

Gnomad4 AMR AF: 0.375

Gnomad4 ASJ AF: 0.204

Gnomad4 EAS AF: 0.651

Gnomad4 SAS AF: 0.432

Gnomad4 FIN AF: 0.204

Gnomad4 NFE AF: 0.207

Gnomad4 OTH AF: 0.318

Alfa AF: 0.263 Hom.: 1444

Bravo AF: 0.368

Asia WGS AF: 0.544 AC: 1891 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.5
DANN	Benign	0.55
BranchPoint Hunter		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2742327; hg19: chr2-179587687; COSMIC: COSV59864550; COSMIC: COSV59864550;