2-178740453-C-A

Variant names:

• chr2-178740453-C-A
• rs746578
• NM_001267550.2:c.12780G>T

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>T​(p.Ala4260Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0527 in 1,613,230 control chromosomes in the GnomAD database, including 3,833 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 0.050 (381 hom., cov: 32)
  • Exomes 𝑓: 0.053 (3452 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20
• 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=-0.77).
• BP6: Variant 2-178740453-C-A is Benign according to our data. Variant chr2-178740453-C-A is described in ClinVar as Benign. ClinVar VariationId is 47831.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 = 0.179 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>T	p.Ala4260Ala	synonymous	Exon 48 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.11829G>T	p.Ala3943Ala	synonymous	Exon 46 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133437.4		c.12267G>T	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>T	p.Ala4260Ala	synonymous	Exon 48 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.12780G>T	p.Ala4260Ala	synonymous	Exon 48 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.12504G>T	p.Ala4168Ala	synonymous	Exon 46 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0501 AC: 7612 AN: 151978 Hom.: 380 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.0484

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.0487

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.0237

Gnomad FIN AF: 0.0515

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0454

Gnomad OTH AF: 0.0465

GnomAD2 exomes AF: 0.0795 AC: 19697 AN: 247814 AF XY: 0.0700

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.241

Gnomad ASJ exome AF: 0.0485

Gnomad EAS exome AF: 0.208

Gnomad FIN exome AF: 0.0521

Gnomad NFE exome AF: 0.0444

Gnomad OTH exome AF: 0.0671

GnomAD4 exome AF: 0.0530 AC: 77372 AN: 1461134 Hom.: 3452 Cov.: 33 AF XY: 0.0512 AC XY: 37191 AN XY: 726796

African (AFR) AF: 0.00932 AC: 312 AN: 33472

American (AMR) AF: 0.229 AC: 10209 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.0474 AC: 1237 AN: 26122

East Asian (EAS) AF: 0.189 AC: 7482 AN: 39592

South Asian (SAS) AF: 0.0201 AC: 1731 AN: 86216

European-Finnish (FIN) AF: 0.0546 AC: 2912 AN: 53370

Middle Eastern (MID) AF: 0.0161 AC: 93 AN: 5760

European-Non Finnish (NFE) AF: 0.0452 AC: 50280 AN: 1111616

Other (OTH) AF: 0.0516 AC: 3116 AN: 60330

GnomAD4 genome AF: 0.0501 AC: 7615 AN: 152096 Hom.: 381 Cov.: 32 AF XY: 0.0517 AC XY: 3840 AN XY: 74338

African (AFR) AF: 0.0116 AC: 481 AN: 41498

American (AMR) AF: 0.138 AC: 2106 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0487 AC: 169 AN: 3472

East Asian (EAS) AF: 0.189 AC: 973 AN: 5144

South Asian (SAS) AF: 0.0230 AC: 111 AN: 4816

European-Finnish (FIN) AF: 0.0515 AC: 545 AN: 10580

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0454 AC: 3086 AN: 68002

Other (OTH) AF: 0.0451 AC: 95 AN: 2108

Alfa AF: 0.0118 Hom.: 628

EpiCase AF: 0.0407

EpiControl AF: 0.0430

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	3	not provided (3)
-	-	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	-0.77
CADD	Benign	0.19
DANN	Benign	0.73
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: COSV60241877; COSMIC: COSV60241877;