2-178531231-T-C

Variant names:

• chr2-178531231-T-C
• rs3813250
• NM_001267550.2:c.105384A>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.105384A>G​(p.Ala35128Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,613,596 control chromosomes in the GnomAD database, including 74,784 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. A35128A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.36 (11862 hom., cov: 32)
  • Exomes 𝑓: 0.27 (62922 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 0.0550
• Publications: 28 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=-0.63).
• BP6: Variant 2-178531231-T-C is Benign according to our data. Variant chr2-178531231-T-C is described in ClinVar as Benign. ClinVar VariationId is 47689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.055 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.679 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.105384A>G	p.Ala35128Ala	synonymous	Exon 358 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.100461A>G	p.Ala33487Ala	synonymous	Exon 308 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.97680A>G	p.Ala32560Ala	synonymous	Exon 307 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.105384A>G	p.Ala35128Ala	synonymous	Exon 358 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.105228A>G	p.Ala35076Ala	synonymous	Exon 356 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.105108A>G	p.Ala35036Ala	synonymous	Exon 356 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.362 AC: 54926 AN: 151786 Hom.: 11813 Cov.: 32

Gnomad AFR AF: 0.542

Gnomad AMI AF: 0.561

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.698

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.329

GnomAD2 exomes AF: 0.352 AC: 87725 AN: 249054 AF XY: 0.349

Gnomad AFR exome AF: 0.545

Gnomad AMR exome AF: 0.427

Gnomad ASJ exome AF: 0.281

Gnomad EAS exome AF: 0.703

Gnomad FIN exome AF: 0.278

Gnomad NFE exome AF: 0.226

Gnomad OTH exome AF: 0.307

GnomAD4 exome AF: 0.269 AC: 392498 AN: 1461692 Hom.: 62922 Cov.: 64 AF XY: 0.274 AC XY: 198916 AN XY: 727130

African (AFR) AF: 0.557 AC: 18637 AN: 33478

American (AMR) AF: 0.426 AC: 19055 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 7314 AN: 26136

East Asian (EAS) AF: 0.692 AC: 27462 AN: 39700

South Asian (SAS) AF: 0.503 AC: 43413 AN: 86258

European-Finnish (FIN) AF: 0.277 AC: 14792 AN: 53398

Middle Eastern (MID) AF: 0.308 AC: 1778 AN: 5768

European-Non Finnish (NFE) AF: 0.217 AC: 241757 AN: 1111858

Other (OTH) AF: 0.303 AC: 18290 AN: 60374

GnomAD4 genome AF: 0.362 AC: 55035 AN: 151904 Hom.: 11862 Cov.: 32 AF XY: 0.372 AC XY: 27623 AN XY: 74240

African (AFR) AF: 0.543 AC: 22484 AN: 41398

American (AMR) AF: 0.385 AC: 5881 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 983 AN: 3466

East Asian (EAS) AF: 0.698 AC: 3587 AN: 5138

South Asian (SAS) AF: 0.514 AC: 2474 AN: 4812

European-Finnish (FIN) AF: 0.285 AC: 3013 AN: 10572

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

European-Non Finnish (NFE) AF: 0.225 AC: 15305 AN: 67946

Other (OTH) AF: 0.337 AC: 711 AN: 2110

Alfa AF: 0.264 Hom.: 12817

Bravo AF: 0.376

Asia WGS AF: 0.618 AC: 2149 AN: 3478

EpiCase AF: 0.220

EpiControl AF: 0.230

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	-0.63
CADD	Benign	0.013
DANN	Benign	0.56
PhyloP100		0.055
Mutation Taster		=98/2	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: rs3813250; hg19: chr2-179395958; COSMIC: COSV60092245; COSMIC: COSV60092245;