2-178570610-T-G

Variant names:

• chr2-178570610-T-G
• rs6732060
• NM_001267550.2:c.75522A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.75522A>C​(p.Ala25174Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0589 in 1,613,380 control chromosomes in the GnomAD database, including 5,781 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. A25174A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1426 hom., cov: 32)
  • Exomes 𝑓: 0.054 (4355 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 0.117
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 2-178570610-T-G is Benign according to our data. Variant chr2-178570610-T-G is described in ClinVar as Benign. ClinVar VariationId is 47339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 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.75522A>C	p.Ala25174Ala	synonymous	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.70599A>C	p.Ala23533Ala	synonymous	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.67818A>C	p.Ala22606Ala	synonymous	Exon 275 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.75522A>C	p.Ala25174Ala	synonymous	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.75366A>C	p.Ala25122Ala	synonymous	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.75246A>C	p.Ala25082Ala	synonymous	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15953 AN: 152008 Hom.: 1402 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.0247

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.0587

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0335

Gnomad OTH AF: 0.0863

GnomAD2 exomes AF: 0.0913 AC: 22676 AN: 248390 AF XY: 0.0875

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.209

Gnomad ASJ exome AF: 0.0354

Gnomad EAS exome AF: 0.0276

Gnomad FIN exome AF: 0.0579

Gnomad NFE exome AF: 0.0353

Gnomad OTH exome AF: 0.0703

GnomAD4 exome AF: 0.0540 AC: 78968 AN: 1461252 Hom.: 4355 Cov.: 44 AF XY: 0.0561 AC XY: 40812 AN XY: 726910

African (AFR) AF: 0.225 AC: 7511 AN: 33450

American (AMR) AF: 0.206 AC: 9208 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 948 AN: 26128

East Asian (EAS) AF: 0.0137 AC: 542 AN: 39604

South Asian (SAS) AF: 0.175 AC: 15079 AN: 86244

European-Finnish (FIN) AF: 0.0593 AC: 3167 AN: 53384

Middle Eastern (MID) AF: 0.0592 AC: 341 AN: 5758

European-Non Finnish (NFE) AF: 0.0344 AC: 38233 AN: 1111634

Other (OTH) AF: 0.0653 AC: 3939 AN: 60352

GnomAD4 genome AF: 0.105 AC: 16029 AN: 152128 Hom.: 1426 Cov.: 32 AF XY: 0.111 AC XY: 8271 AN XY: 74356

African (AFR) AF: 0.216 AC: 8973 AN: 41498

American (AMR) AF: 0.183 AC: 2801 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 125 AN: 3468

East Asian (EAS) AF: 0.0250 AC: 129 AN: 5160

South Asian (SAS) AF: 0.177 AC: 853 AN: 4822

European-Finnish (FIN) AF: 0.0587 AC: 623 AN: 10620

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0335 AC: 2276 AN: 67980

Other (OTH) AF: 0.0854 AC: 180 AN: 2108

Alfa AF: 0.0546 Hom.: 845

Bravo AF: 0.115

Asia WGS AF: 0.128 AC: 445 AN: 3478

EpiCase AF: 0.0331

EpiControl AF: 0.0342

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	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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.48
DANN	Benign	0.69
PhyloP100		0.12
Mutation Taster		=96/4	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: rs6732060; hg19: chr2-179435337; COSMIC: COSV60092430;