rs2291306

Variant names:

• chr2-178773511-G-A
• rs2291306
• NM_001267550.2:c.7545C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001267550.2(TTN):​c.7545C>T​(p.Tyr2515Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,613,940 control chromosomes in the GnomAD database, including 9,483 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (667 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8816 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 1.40
• Publications: 14 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 2-178773511-G-A is Benign according to our data. Variant chr2-178773511-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.11 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.7545C>T	p.Tyr2515Tyr	synonymous	Exon 32 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.7545C>T	p.Tyr2515Tyr	synonymous	Exon 32 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.7545C>T	p.Tyr2515Tyr	synonymous	Exon 32 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.7545C>T	p.Tyr2515Tyr	synonymous	Exon 32 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.7545C>T	p.Tyr2515Tyr	synonymous	Exon 32 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.7269C>T	p.Tyr2423Tyr	synonymous	Exon 30 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0923 AC: 14038 AN: 152100 Hom.: 667 Cov.: 32

Gnomad AFR AF: 0.0752

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0692

Gnomad ASJ AF: 0.0674

Gnomad EAS AF: 0.0241

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0992

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.0928

GnomAD2 exomes AF: 0.0901 AC: 22615 AN: 250928 AF XY: 0.0944

Gnomad AFR exome AF: 0.0760

Gnomad AMR exome AF: 0.0464

Gnomad ASJ exome AF: 0.0709

Gnomad EAS exome AF: 0.0222

Gnomad FIN exome AF: 0.0987

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.0962

GnomAD4 exome AF: 0.107 AC: 156338 AN: 1461722 Hom.: 8816 Cov.: 33 AF XY: 0.107 AC XY: 78124 AN XY: 727174

African (AFR) AF: 0.0704 AC: 2355 AN: 33474

American (AMR) AF: 0.0492 AC: 2200 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0704 AC: 1841 AN: 26134

East Asian (EAS) AF: 0.0217 AC: 859 AN: 39674

South Asian (SAS) AF: 0.109 AC: 9394 AN: 86254

European-Finnish (FIN) AF: 0.0984 AC: 5256 AN: 53394

Middle Eastern (MID) AF: 0.104 AC: 597 AN: 5768

European-Non Finnish (NFE) AF: 0.115 AC: 127752 AN: 1111926

Other (OTH) AF: 0.101 AC: 6084 AN: 60388

GnomAD4 genome AF: 0.0923 AC: 14048 AN: 152218 Hom.: 667 Cov.: 32 AF XY: 0.0917 AC XY: 6822 AN XY: 74414

African (AFR) AF: 0.0750 AC: 3117 AN: 41538

American (AMR) AF: 0.0691 AC: 1056 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0674 AC: 234 AN: 3470

East Asian (EAS) AF: 0.0241 AC: 125 AN: 5176

South Asian (SAS) AF: 0.106 AC: 511 AN: 4824

European-Finnish (FIN) AF: 0.0992 AC: 1052 AN: 10602

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7639 AN: 68000

Other (OTH) AF: 0.0919 AC: 194 AN: 2112

Alfa AF: 0.104 Hom.: 1081

Bravo AF: 0.0876

Asia WGS AF: 0.0680 AC: 235 AN: 3476

EpiCase AF: 0.110

EpiControl AF: 0.109

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	-0.52
CADD	Benign	3.7
DANN	Benign	0.77
PhyloP100		1.4
Mutation Taster		=78/22	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2291306; hg19: chr2-179638238; COSMIC: COSV60330709; COSMIC: COSV60330709;