chr2-178747124-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_133379.5(TTN):c.15276G>A(p.Leu5092Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00483 in 1,555,344 control chromosomes in the GnomAD database, including 457 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 293 hom., cov: 31)

Exomes 𝑓: 0.0021 ( 164 hom. )

Consequence

TTN
NM_133379.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.40

Publications

5 publications found

Variant links:

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 links:

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]

TTN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 2-178747124-C-T is Benign according to our data. Variant chr2-178747124-C-T is described in ClinVar as Benign. ClinVar VariationId is 47782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.4 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_133379.5 link	c.15276G>A	p.Leu5092Leu	synonymous_variant	Exon 46 of 46	ENST00000360870.10	NP_596870.2	Q8WZ42-6Q7Z3B7
TTN	NM_001267550.2 link	c.11312-5203G>A		intron_variant	Intron 47 of 362	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000360870.10 link	c.15276G>A	p.Leu5092Leu	synonymous_variant	Exon 46 of 46	5	NM_133379.5	ENSP00000354117.4		Q8WZ42-6
TTN	ENST00000589042.5 link	c.11312-5203G>A		intron_variant	Intron 47 of 362	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.0383

AC:

4523

AN:

118132

Hom.:

294

Cov.:

show subpopulations

Gnomad AFR

AF:

0.137

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000502

Gnomad SAS

AF:

0.000821

Gnomad FIN

AF:

0.000139

Gnomad MID

AF:

0.0217

Gnomad NFE

AF:

0.000726

Gnomad OTH

AF:

0.0368

GnomAD2 exomes

AF:

0.00530

AC:

1294

AN:

244026

AF XY:

0.00401

show subpopulations

Gnomad AFR exome

AF:

0.0750

Gnomad AMR exome

AF:

0.00280

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000471

Gnomad NFE exome

AF:

0.000289

Gnomad OTH exome

AF:

0.00306

GnomAD4 exome

AF:

0.00206

AC:

2964

AN:

1437104

Hom.:

164

Cov.:

AF XY:

0.00176

AC XY:

1258

AN XY:

715440

show subpopulations

African (AFR)

AF:

0.0775

AC:

2305

AN:

29738

American (AMR)

AF:

0.00339

AC:

147

AN:

43356

Ashkenazi Jewish (ASJ)

AF:

0.0000781

AC:

AN:

25604

East Asian (EAS)

AF:

0.00

AC:

AN:

39220

South Asian (SAS)

AF:

0.000222

AC:

AN:

85524

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52784

Middle Eastern (MID)

AF:

0.00269

AC:

AN:

5582

European-Non Finnish (NFE)

AF:

0.000114

AC:

125

AN:

1096120

Other (OTH)

AF:

0.00591

AC:

350

AN:

59176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.411

Heterozygous variant carriers

114

228

343

457

571

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0384

AC:

4545

AN:

118240

Hom.:

293

Cov.:

AF XY:

0.0366

AC XY:

2087

AN XY:

57018

show subpopulations

African (AFR)

AF:

0.138

AC:

4299

AN:

31248

American (AMR)

AF:

0.0115

AC:

135

AN:

11728

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2908

East Asian (EAS)

AF:

0.000503

AC:

AN:

3978

South Asian (SAS)

AF:

0.00110

AC:

AN:

3652

European-Finnish (FIN)

AF:

0.000139

AC:

AN:

7212

Middle Eastern (MID)

AF:

0.0227

AC:

AN:

176

European-Non Finnish (NFE)

AF:

0.000726

AC:

AN:

55060

Other (OTH)

AF:

0.0365

AC:

AN:

1646

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

174

348

522

696

870

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0246

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Mar 05, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter