rs2366753

Variant names:

• chr2-178702907-T-C
• rs2366753
• NM_001267550.2:c.30224-244A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001267550.2(TTN):​c.30224-244A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 152,156 control chromosomes in the GnomAD database, including 1,827 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.11 (1827 hom., cov: 32)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0960
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-178702907-T-C is Benign according to our data. Variant chr2-178702907-T-C is described in ClinVar as Benign. ClinVar VariationId is 672587.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.30224-244A>G		intron	N/A	NP_001254479.2
	TTN	NM_001256850.1		c.29273-244A>G		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.26492-244A>G		intron	N/A	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.30224-244A>G		intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.30224-244A>G		intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.29948-244A>G		intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16812 AN: 152040 Hom.: 1806 Cov.: 32

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.0572

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0263

Gnomad OTH AF: 0.0849

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

GnomAD4 genome AF: 0.111 AC: 16880 AN: 152156 Hom.: 1827 Cov.: 32 AF XY: 0.115 AC XY: 8540 AN XY: 74430

African (AFR) AF: 0.260 AC: 10782 AN: 41456

American (AMR) AF: 0.158 AC: 2418 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0317 AC: 110 AN: 3470

East Asian (EAS) AF: 0.0239 AC: 124 AN: 5188

South Asian (SAS) AF: 0.169 AC: 816 AN: 4822

European-Finnish (FIN) AF: 0.0572 AC: 607 AN: 10608

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0263 AC: 1789 AN: 68012

Other (OTH) AF: 0.0840 AC: 177 AN: 2108

Alfa AF: 0.104 Hom.: 293

Bravo AF: 0.123

Asia WGS AF: 0.126 AC: 436 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.4
DANN	Benign	0.66
PhyloP100		-0.096
PromoterAI		0.0014	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2366753; hg19: chr2-179567634;