rs55863869

Variant names:

• chr2-178782819-A-G
• rs55863869
• NM_001267550.2:c.3087T>C
• TTN p.Tyr1029Tyr

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.3087T>C​(p.Tyr1029Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0557 in 1,613,014 control chromosomes in the GnomAD database, including 4,069 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (395 hom., cov: 32)
  • Exomes 𝑓: 0.056 (3674 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 0.766
• Publications: 13 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
• myopathy, myofibrillar, 9, with early respiratory failure

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

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

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 2-178782819-A-G is Benign according to our data. Variant chr2-178782819-A-G is described in ClinVar as Benign. ClinVar VariationId is 46907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.179 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.3087T>C	p.Tyr1029Tyr	synonymous	Exon 18 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.3087T>C	p.Tyr1029Tyr	synonymous	Exon 18 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.3087T>C	p.Tyr1029Tyr	synonymous	Exon 18 of 312	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.3087T>C	p.Tyr1029Tyr	synonymous	Exon 18 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.3087T>C	p.Tyr1029Tyr	synonymous	Exon 18 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.2811T>C	p.Tyr937Tyr	synonymous	Exon 16 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0529 AC: 8055 AN: 152204 Hom.: 394 Cov.: 32

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.0496

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.0568

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0501

Gnomad OTH AF: 0.0473

GnomAD2 exomes AF: 0.0817 AC: 20468 AN: 250464 AF XY: 0.0725

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.241

Gnomad ASJ exome AF: 0.0497

Gnomad EAS exome AF: 0.204

Gnomad FIN exome AF: 0.0589

Gnomad NFE exome AF: 0.0484

Gnomad OTH exome AF: 0.0680

GnomAD4 exome AF: 0.0560 AC: 81731 AN: 1460692 Hom.: 3674 Cov.: 32 AF XY: 0.0540 AC XY: 39257 AN XY: 726694

African (AFR) AF: 0.00984 AC: 329 AN: 33446

American (AMR) AF: 0.229 AC: 10231 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0488 AC: 1276 AN: 26132

East Asian (EAS) AF: 0.192 AC: 7635 AN: 39670

South Asian (SAS) AF: 0.0203 AC: 1747 AN: 86200

European-Finnish (FIN) AF: 0.0619 AC: 3303 AN: 53398

Middle Eastern (MID) AF: 0.0178 AC: 90 AN: 5062

European-Non Finnish (NFE) AF: 0.0484 AC: 53852 AN: 1111814

Other (OTH) AF: 0.0542 AC: 3268 AN: 60274

GnomAD4 genome AF: 0.0529 AC: 8060 AN: 152322 Hom.: 395 Cov.: 32 AF XY: 0.0544 AC XY: 4054 AN XY: 74488

African (AFR) AF: 0.0122 AC: 506 AN: 41594

American (AMR) AF: 0.140 AC: 2141 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0496 AC: 172 AN: 3470

East Asian (EAS) AF: 0.188 AC: 975 AN: 5174

South Asian (SAS) AF: 0.0228 AC: 110 AN: 4830

European-Finnish (FIN) AF: 0.0568 AC: 603 AN: 10616

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0501 AC: 3406 AN: 68020

Other (OTH) AF: 0.0464 AC: 98 AN: 2114

Alfa AF: 0.0482 Hom.: 114

Bravo AF: 0.0629

Asia WGS AF: 0.0780 AC: 270 AN: 3478

EpiCase AF: 0.0440

EpiControl AF: 0.0459

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	2.8
DANN	Benign	0.60
PhyloP100		0.77
Mutation Taster		=89/11	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs55863869;

hg19: chr2-179647546;

COSMIC: COSV60014407;

COSMIC: COSV60014407;