2-178786523-T-C

Position:

• chr2-178786523-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001267550.2(TTN):​c.2077-382A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 152,216 control chromosomes in the GnomAD database, including 1,873 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 0.13 (1873 hom., cov: 32)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.138

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.2077-382A>G		intron_variant		ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.2077-382A>G		intron_variant		ENST00000360870.10	NP_596870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000360870.10	c.2077-382A>G		intron_variant		5	NM_133379.5	ENSP00000354117
TTN	ENST00000589042.5	c.2077-382A>G		intron_variant		5	NM_001267550.2	ENSP00000467141	P1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20431 AN: 152098 Hom.: 1873 Cov.: 32

Gnomad AFR AF: 0.0411

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0557

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.184

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

GnomAD4 genome AF: 0.134 AC: 20418 AN: 152216 Hom.: 1873 Cov.: 32 AF XY: 0.129 AC XY: 9583 AN XY: 74416

Gnomad4 AFR AF: 0.0410

Gnomad4 AMR AF: 0.143

Gnomad4 ASJ AF: 0.274

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0553

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.201

Gnomad4 OTH AF: 0.182

Alfa AF: 0.179 Hom.: 1247

Bravo AF: 0.135

Asia WGS AF: 0.0290 AC: 102 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.1
DANN	Benign	0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs10497521; hg19: chr2-179651250;