2-178609739-C-T

Variant names:

• chr2-178609739-C-T
• rs2288566
• NM_001267550.2:c.51684G>A

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.51684G>A​(p.Ala17228Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0234 in 1,611,852 control chromosomes in the GnomAD database, including 620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (64 hom., cov: 32)
  • Exomes 𝑓: 0.024 (556 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: -0.177
• Publications: 6 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=-0.56).
• BP6: Variant 2-178609739-C-T is Benign according to our data. Variant chr2-178609739-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.177 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0859 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.51684G>A	p.Ala17228Ala	synonymous	Exon 272 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.46761G>A	p.Ala15587Ala	synonymous	Exon 222 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.43980G>A	p.Ala14660Ala	synonymous	Exon 221 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.51684G>A	p.Ala17228Ala	synonymous	Exon 272 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.51528G>A	p.Ala17176Ala	synonymous	Exon 270 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.51408G>A	p.Ala17136Ala	synonymous	Exon 270 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3216 AN: 151898 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0228

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.0926

Gnomad SAS AF: 0.00769

Gnomad FIN AF: 0.0447

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0230

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.0286 AC: 7080 AN: 247466 AF XY: 0.0269

Gnomad AFR exome AF: 0.00486

Gnomad AMR exome AF: 0.0331

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.0994

Gnomad FIN exome AF: 0.0466

Gnomad NFE exome AF: 0.0231

Gnomad OTH exome AF: 0.0275

GnomAD4 exome AF: 0.0236 AC: 34442 AN: 1459836 Hom.: 556 Cov.: 32 AF XY: 0.0231 AC XY: 16769 AN XY: 726122

African (AFR) AF: 0.00404 AC: 135 AN: 33386

American (AMR) AF: 0.0316 AC: 1413 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 374 AN: 26054

East Asian (EAS) AF: 0.0898 AC: 3559 AN: 39616

South Asian (SAS) AF: 0.00688 AC: 592 AN: 86062

European-Finnish (FIN) AF: 0.0481 AC: 2566 AN: 53326

Middle Eastern (MID) AF: 0.0101 AC: 58 AN: 5754

European-Non Finnish (NFE) AF: 0.0219 AC: 24330 AN: 1110670

Other (OTH) AF: 0.0235 AC: 1415 AN: 60282

GnomAD4 genome AF: 0.0211 AC: 3213 AN: 152016 Hom.: 64 Cov.: 32 AF XY: 0.0216 AC XY: 1606 AN XY: 74280

African (AFR) AF: 0.00436 AC: 181 AN: 41518

American (AMR) AF: 0.0228 AC: 348 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3468

East Asian (EAS) AF: 0.0928 AC: 476 AN: 5130

South Asian (SAS) AF: 0.00707 AC: 34 AN: 4810

European-Finnish (FIN) AF: 0.0447 AC: 474 AN: 10596

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0230 AC: 1559 AN: 67920

Other (OTH) AF: 0.0213 AC: 45 AN: 2112

Alfa AF: 0.0208 Hom.: 50

Bravo AF: 0.0197

Asia WGS AF: 0.0350 AC: 122 AN: 3478

EpiCase AF: 0.0196

EpiControl AF: 0.0216

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	3	not provided (3)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.2
DANN	Benign	0.83
PhyloP100		-0.18
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs2288566; hg19: chr2-179474466; COSMIC: COSV60187912; COSMIC: COSV60187912;