NM_001267550.2:c.62058T>C

Variant names:

• chr2-178589667-A-G
• rs1560221
• NM_001267550.2:c.62058T>C

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.62058T>C​(p.Tyr20686Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 1,613,264 control chromosomes in the GnomAD database, including 75,643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11907 hom., cov: 33)
  • Exomes 𝑓: 0.27 (63736 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 0.156
• Publications: 26 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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 2-178589667-A-G is Benign according to our data. Variant chr2-178589667-A-G is described in ClinVar as Benign. ClinVar VariationId is 47179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.689 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.62058T>C	p.Tyr20686Tyr	synonymous	Exon 304 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.57135T>C	p.Tyr19045Tyr	synonymous	Exon 254 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.54354T>C	p.Tyr18118Tyr	synonymous	Exon 253 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.62058T>C	p.Tyr20686Tyr	synonymous	Exon 304 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.61902T>C	p.Tyr20634Tyr	synonymous	Exon 302 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.61782T>C	p.Tyr20594Tyr	synonymous	Exon 302 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55095 AN: 151850 Hom.: 11858 Cov.: 33

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.558

Gnomad AMR AF: 0.387

Gnomad ASJ AF: 0.290

Gnomad EAS AF: 0.708

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.332

GnomAD2 exomes AF: 0.355 AC: 88015 AN: 247958 AF XY: 0.352

Gnomad AFR exome AF: 0.543

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.288

Gnomad EAS exome AF: 0.711

Gnomad FIN exome AF: 0.278

Gnomad NFE exome AF: 0.227

Gnomad OTH exome AF: 0.310

GnomAD4 exome AF: 0.270 AC: 394772 AN: 1461298 Hom.: 63736 Cov.: 38 AF XY: 0.275 AC XY: 200198 AN XY: 726926

African (AFR) AF: 0.554 AC: 18523 AN: 33454

American (AMR) AF: 0.429 AC: 19174 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 7521 AN: 26120

East Asian (EAS) AF: 0.698 AC: 27681 AN: 39654

South Asian (SAS) AF: 0.509 AC: 43901 AN: 86234

European-Finnish (FIN) AF: 0.278 AC: 14824 AN: 53388

Middle Eastern (MID) AF: 0.316 AC: 1823 AN: 5760

European-Non Finnish (NFE) AF: 0.219 AC: 242895 AN: 1111624

Other (OTH) AF: 0.305 AC: 18430 AN: 60352

GnomAD4 genome AF: 0.363 AC: 55205 AN: 151966 Hom.: 11907 Cov.: 33 AF XY: 0.373 AC XY: 27724 AN XY: 74244

African (AFR) AF: 0.541 AC: 22413 AN: 41452

American (AMR) AF: 0.388 AC: 5912 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 1007 AN: 3470

East Asian (EAS) AF: 0.709 AC: 3622 AN: 5112

South Asian (SAS) AF: 0.520 AC: 2505 AN: 4818

European-Finnish (FIN) AF: 0.286 AC: 3029 AN: 10598

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15405 AN: 67944

Other (OTH) AF: 0.340 AC: 720 AN: 2116

Alfa AF: 0.276 Hom.: 14554

Bravo AF: 0.377

Asia WGS AF: 0.618 AC: 2148 AN: 3478

EpiCase AF: 0.221

EpiControl AF: 0.232

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	not provided (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.11
DANN	Benign	0.72
PhyloP100		0.16
Mutation Taster		=88/12	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: rs1560221; hg19: chr2-179454394; COSMIC: COSV60092491; COSMIC: COSV60092491;