2-178740453-C-T

Variant names:

• chr2-178740453-C-T
• rs746578
• NM_001267550.2:c.12780G>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.12780G>A​(p.Ala4260Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,613,234 control chromosomes in the GnomAD database, including 20,284 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. A4260A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.16 (2230 hom., cov: 32)
  • Exomes 𝑓: 0.14 (18054 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.0990
• Publications: 24 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=-0.83).
• BP6: Variant 2-178740453-C-T is Benign according to our data. Variant chr2-178740453-C-T is described in ClinVar as Benign. ClinVar VariationId is 47830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.099 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.445 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.12780G>A	p.Ala4260Ala	synonymous	Exon 48 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.11829G>A	p.Ala3943Ala	synonymous	Exon 46 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133437.4		c.12267G>A	p.Ala4089Ala	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.12780G>A	p.Ala4260Ala	synonymous	Exon 48 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.12780G>A	p.Ala4260Ala	synonymous	Exon 48 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.12504G>A	p.Ala4168Ala	synonymous	Exon 46 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23557 AN: 151956 Hom.: 2226 Cov.: 32

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.0958

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.156

GnomAD2 exomes AF: 0.164 AC: 40576 AN: 247814 AF XY: 0.165

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.462

Gnomad FIN exome AF: 0.0946

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.144 AC: 210847 AN: 1461160 Hom.: 18054 Cov.: 33 AF XY: 0.146 AC XY: 105862 AN XY: 726818

African (AFR) AF: 0.162 AC: 5422 AN: 33470

American (AMR) AF: 0.144 AC: 6427 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 3008 AN: 26122

East Asian (EAS) AF: 0.472 AC: 18691 AN: 39596

South Asian (SAS) AF: 0.203 AC: 17476 AN: 86216

European-Finnish (FIN) AF: 0.0916 AC: 4890 AN: 53374

Middle Eastern (MID) AF: 0.195 AC: 1124 AN: 5760

European-Non Finnish (NFE) AF: 0.130 AC: 144537 AN: 1111618

Other (OTH) AF: 0.154 AC: 9272 AN: 60338

GnomAD4 genome AF: 0.155 AC: 23575 AN: 152074 Hom.: 2230 Cov.: 32 AF XY: 0.157 AC XY: 11649 AN XY: 74322

African (AFR) AF: 0.159 AC: 6603 AN: 41492

American (AMR) AF: 0.153 AC: 2331 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 417 AN: 3472

East Asian (EAS) AF: 0.461 AC: 2370 AN: 5142

South Asian (SAS) AF: 0.205 AC: 986 AN: 4812

European-Finnish (FIN) AF: 0.0958 AC: 1013 AN: 10578

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9066 AN: 67994

Other (OTH) AF: 0.161 AC: 339 AN: 2106

Alfa AF: 0.141 Hom.: 628

EpiCase AF: 0.133

EpiControl AF: 0.138

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	not provided (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.3
DANN	Benign	0.78
PhyloP100		-0.099
Mutation Taster		=99/1	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: rs746578; hg19: chr2-179605180; COSMIC: COSV60101823; COSMIC: COSV60101823;