NM_001267550.2:c.29763T>C

Variant names:

• chr2-178704709-A-G
• rs2742343
• NM_001267550.2:c.29763T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001267550.2(TTN):​c.29763T>C​(p.Ile9921Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0368 in 1,611,202 control chromosomes in the GnomAD database, including 2,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (557 hom., cov: 33)
  • Exomes 𝑓: 0.034 (1692 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 1.82
• Publications: 9 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 2-178704709-A-G is Benign according to our data. Variant chr2-178704709-A-G is described in ClinVar as Benign. ClinVar VariationId is 46823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.82 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.181 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.29763T>C	p.Ile9921Ile	synonymous	Exon 105 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.28812T>C	p.Ile9604Ile	synonymous	Exon 103 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.26031T>C	p.Ile8677Ile	synonymous	Exon 102 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.29763T>C	p.Ile9921Ile	synonymous	Exon 105 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.29763T>C	p.Ile9921Ile	synonymous	Exon 105 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.29487T>C	p.Ile9829Ile	synonymous	Exon 103 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0656 AC: 9987 AN: 152162 Hom.: 556 Cov.: 33

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0443

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.0366

Gnomad FIN AF: 0.0475

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0259

Gnomad OTH AF: 0.0588

GnomAD2 exomes AF: 0.0526 AC: 12906 AN: 245366 AF XY: 0.0484

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.0486

Gnomad ASJ exome AF: 0.0320

Gnomad EAS exome AF: 0.210

Gnomad FIN exome AF: 0.0500

Gnomad NFE exome AF: 0.0260

Gnomad OTH exome AF: 0.0406

GnomAD4 exome AF: 0.0337 AC: 49212 AN: 1458922 Hom.: 1692 Cov.: 32 AF XY: 0.0332 AC XY: 24069 AN XY: 725686

African (AFR) AF: 0.134 AC: 4479 AN: 33448

American (AMR) AF: 0.0473 AC: 2106 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 849 AN: 26098

East Asian (EAS) AF: 0.191 AC: 7565 AN: 39676

South Asian (SAS) AF: 0.0306 AC: 2637 AN: 86104

European-Finnish (FIN) AF: 0.0515 AC: 2667 AN: 51806

Middle Eastern (MID) AF: 0.0206 AC: 119 AN: 5764

European-Non Finnish (NFE) AF: 0.0237 AC: 26354 AN: 1111202

Other (OTH) AF: 0.0404 AC: 2436 AN: 60304

GnomAD4 genome AF: 0.0657 AC: 10004 AN: 152280 Hom.: 557 Cov.: 33 AF XY: 0.0661 AC XY: 4923 AN XY: 74476

African (AFR) AF: 0.135 AC: 5617 AN: 41542

American (AMR) AF: 0.0443 AC: 677 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 127 AN: 3470

East Asian (EAS) AF: 0.191 AC: 988 AN: 5186

South Asian (SAS) AF: 0.0366 AC: 177 AN: 4832

European-Finnish (FIN) AF: 0.0475 AC: 504 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0259 AC: 1760 AN: 68022

Other (OTH) AF: 0.0572 AC: 121 AN: 2114

Alfa AF: 0.0368 Hom.: 217

Bravo AF: 0.0703

Asia WGS AF: 0.0870 AC: 300 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	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	-0.42
CADD	Benign	3.0
DANN	Benign	0.83
PhyloP100		1.8
Mutation Taster		=75/25	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: rs2742343; hg19: chr2-179569436; COSMIC: COSV59946373; COSMIC: COSV59946373;