rs2742357

Variant names:

• chr2-178740978-A-G
• rs2742357
• NM_001267550.2:c.12255T>C

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.12255T>C​(p.Ile4085Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0527 in 1,613,866 control chromosomes in the GnomAD database, including 3,840 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (377 hom., cov: 32)
  • Exomes 𝑓: 0.053 (3463 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0280
• Publications: 11 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=-0.62).
• BP6: Variant 2-178740978-A-G is Benign according to our data. Variant chr2-178740978-A-G is described in ClinVar as Benign. ClinVar VariationId is 47824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.028 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.178 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.12255T>C	p.Ile4085Ile	synonymous	Exon 48 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.11304T>C	p.Ile3768Ile	synonymous	Exon 46 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133437.4		c.11742T>C	p.Ile3914Ile	synonymous	Exon 46 of 192	NP_597681.4	A0A0A0MRA3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.12255T>C	p.Ile4085Ile	synonymous	Exon 48 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.12255T>C	p.Ile4085Ile	synonymous	Exon 48 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.11979T>C	p.Ile3993Ile	synonymous	Exon 46 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0500 AC: 7607 AN: 152150 Hom.: 376 Cov.: 32

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.0487

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.0512

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0453

Gnomad OTH AF: 0.0463

GnomAD2 exomes AF: 0.0798 AC: 19813 AN: 248302 AF XY: 0.0703

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.241

Gnomad ASJ exome AF: 0.0484

Gnomad EAS exome AF: 0.208

Gnomad FIN exome AF: 0.0524

Gnomad NFE exome AF: 0.0445

Gnomad OTH exome AF: 0.0675

GnomAD4 exome AF: 0.0530 AC: 77449 AN: 1461598 Hom.: 3463 Cov.: 32 AF XY: 0.0512 AC XY: 37232 AN XY: 727088

African (AFR) AF: 0.00932 AC: 312 AN: 33476

American (AMR) AF: 0.229 AC: 10232 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0474 AC: 1238 AN: 26134

East Asian (EAS) AF: 0.189 AC: 7505 AN: 39680

South Asian (SAS) AF: 0.0201 AC: 1731 AN: 86258

European-Finnish (FIN) AF: 0.0546 AC: 2915 AN: 53396

Middle Eastern (MID) AF: 0.0163 AC: 94 AN: 5762

European-Non Finnish (NFE) AF: 0.0452 AC: 50300 AN: 1111816

Other (OTH) AF: 0.0517 AC: 3122 AN: 60366

GnomAD4 genome AF: 0.0500 AC: 7610 AN: 152268 Hom.: 377 Cov.: 32 AF XY: 0.0515 AC XY: 3834 AN XY: 74446

African (AFR) AF: 0.0116 AC: 483 AN: 41578

American (AMR) AF: 0.138 AC: 2102 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0487 AC: 169 AN: 3470

East Asian (EAS) AF: 0.188 AC: 973 AN: 5170

South Asian (SAS) AF: 0.0230 AC: 111 AN: 4828

European-Finnish (FIN) AF: 0.0512 AC: 544 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0454 AC: 3084 AN: 68002

Other (OTH) AF: 0.0449 AC: 95 AN: 2116

Alfa AF: 0.0500 Hom.: 471

Bravo AF: 0.0609

Asia WGS AF: 0.0770 AC: 266 AN: 3478

EpiCase AF: 0.0407

EpiControl AF: 0.0431

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	not provided (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.21
DANN	Benign	0.75
PhyloP100		0.028
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: rs2742357; hg19: chr2-179605705; COSMIC: COSV59946554; COSMIC: COSV59946554;