2-178583121-T-C

Variant names:

• chr2-178583121-T-C
• rs4894029
• NM_001267550.2:c.65682A>G

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.65682A>G​(p.Thr21894Thr) 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 1,610,804 control chromosomes in the GnomAD database, including 75,624 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T21894T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.37 (12056 hom., cov: 32)
  • Exomes 𝑓: 0.27 (63568 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: -1.66
• Publications: 25 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=-0.77).
• BP6: Variant 2-178583121-T-C is Benign according to our data. Variant chr2-178583121-T-C is described in ClinVar as Benign. ClinVar VariationId is 47227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.65 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.683 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.65682A>G	p.Thr21894Thr	synonymous	Exon 313 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.60759A>G	p.Thr20253Thr	synonymous	Exon 263 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.57978A>G	p.Thr19326Thr	synonymous	Exon 262 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.65682A>G	p.Thr21894Thr	synonymous	Exon 313 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.65526A>G	p.Thr21842Thr	synonymous	Exon 311 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.65406A>G	p.Thr21802Thr	synonymous	Exon 311 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55341 AN: 151786 Hom.: 12006 Cov.: 32

Gnomad AFR AF: 0.547

Gnomad AMI AF: 0.561

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.702

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.330

GnomAD2 exomes AF: 0.355 AC: 87026 AN: 245224 AF XY: 0.352

Gnomad AFR exome AF: 0.549

Gnomad AMR exome AF: 0.432

Gnomad ASJ exome AF: 0.289

Gnomad EAS exome AF: 0.705

Gnomad FIN exome AF: 0.278

Gnomad NFE exome AF: 0.227

Gnomad OTH exome AF: 0.309

GnomAD4 exome AF: 0.270 AC: 393832 AN: 1458900 Hom.: 63568 Cov.: 34 AF XY: 0.275 AC XY: 199675 AN XY: 725586

African (AFR) AF: 0.560 AC: 18710 AN: 33404

American (AMR) AF: 0.431 AC: 19138 AN: 44432

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 7535 AN: 26072

East Asian (EAS) AF: 0.695 AC: 27329 AN: 39348

South Asian (SAS) AF: 0.510 AC: 43804 AN: 85938

European-Finnish (FIN) AF: 0.278 AC: 14805 AN: 53260

Middle Eastern (MID) AF: 0.318 AC: 1827 AN: 5754

European-Non Finnish (NFE) AF: 0.218 AC: 242281 AN: 1110472

Other (OTH) AF: 0.306 AC: 18403 AN: 60220

GnomAD4 genome AF: 0.365 AC: 55452 AN: 151904 Hom.: 12056 Cov.: 32 AF XY: 0.375 AC XY: 27837 AN XY: 74228

African (AFR) AF: 0.548 AC: 22690 AN: 41434

American (AMR) AF: 0.388 AC: 5922 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1018 AN: 3470

East Asian (EAS) AF: 0.702 AC: 3588 AN: 5108

South Asian (SAS) AF: 0.521 AC: 2509 AN: 4812

European-Finnish (FIN) AF: 0.285 AC: 3020 AN: 10582

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

European-Non Finnish (NFE) AF: 0.227 AC: 15396 AN: 67932

Other (OTH) AF: 0.338 AC: 712 AN: 2104

Alfa AF: 0.280 Hom.: 12280

Bravo AF: 0.379

Asia WGS AF: 0.620 AC: 2151 AN: 3474

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	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	-0.77
CADD	Benign	0.026
DANN	Benign	0.63
PhyloP100		-1.7
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4894029; hg19: chr2-179447848; COSMIC: COSV60287562; COSMIC: COSV60287562;