chr2-178801286-G-A

Variant names:

• chr2-178801286-G-A
• rs3769862
• NM_001267550.2:c.296-604C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001267550.2(TTN):​c.296-604C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0698 in 152,172 control chromosomes in the GnomAD database, including 848 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 0.070 (848 hom., cov: 32)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.187
• Publications: 0 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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1G

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• early-onset myopathy with fatal cardiomyopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• TTN-related myopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• myopathy, myofibrillar, 9, with early respiratory failure

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• tibial muscular dystrophy

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive limb-girdle muscular dystrophy type 2J

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary skeletal muscle disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy 9

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.296-604C>T		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.296-604C>T		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.296-604C>T		intron	N/A	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.296-604C>T		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.296-604C>T		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.296-604C>T		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 10570 AN: 152054 Hom.: 839 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0432

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.0483

Gnomad FIN AF: 0.0200

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00909

Gnomad OTH AF: 0.0645

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

GnomAD4 genome AF: 0.0698 AC: 10616 AN: 152172 Hom.: 848 Cov.: 32 AF XY: 0.0687 AC XY: 5114 AN XY: 74422

African (AFR) AF: 0.194 AC: 8046 AN: 41474

American (AMR) AF: 0.0433 AC: 662 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3470

East Asian (EAS) AF: 0.127 AC: 658 AN: 5178

South Asian (SAS) AF: 0.0483 AC: 233 AN: 4822

European-Finnish (FIN) AF: 0.0200 AC: 212 AN: 10606

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00910 AC: 619 AN: 68006

Other (OTH) AF: 0.0639 AC: 135 AN: 2114

Alfa AF: 0.0490 Hom.: 69

Bravo AF: 0.0799

Asia WGS AF: 0.0940 AC: 327 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.8
DANN	Benign	0.62
PhyloP100		0.19
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: rs3769862; hg19: chr2-179666013;