chr2-178724514-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001267550.2(TTN):c.20861C>T(p.Ala6954Val) variant causes a missense change. The variant allele was found at a frequency of 0.0317 in 1,600,914 control chromosomes in the GnomAD database, including 2,128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 245 hom., cov: 33)

Exomes 𝑓: 0.032 ( 1883 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:22

Conservation

PhyloP100: 6.55

Publications

14 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:

ENSG00000267784 (HGNC:):

ENSG00000267784 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015490651).

BP6

Variant 2-178724514-G-A is Benign according to our data. Variant chr2-178724514-G-A is described in ClinVar as Benign. ClinVar VariationId is 46677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.126 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTN	NM_001267550.2	MANE Select	c.20861C>T	p.Ala6954Val	missense	Exon 72 of 363	NP_001254479.2
TTN	NM_001256850.1		c.19910C>T	p.Ala6637Val	missense	Exon 70 of 313	NP_001243779.1
TTN	NM_133378.4		c.17129C>T	p.Ala5710Val	missense	Exon 69 of 312	NP_596869.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTN	ENST00000589042.5	TSL:5 MANE Select	c.20861C>T	p.Ala6954Val	missense	Exon 72 of 363	ENSP00000467141.1
TTN	ENST00000446966.2	TSL:1	c.20861C>T	p.Ala6954Val	missense	Exon 72 of 361	ENSP00000408004.2
TTN	ENST00000436599.2	TSL:1	c.20585C>T	p.Ala6862Val	missense	Exon 70 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes

AF:

0.0326

AC:

4950

AN:

152002

Hom.:

241

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00659

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.130

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.00155

Gnomad SAS

AF:

0.124

Gnomad FIN

AF:

0.0567

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0194

Gnomad OTH

AF:

0.0287

GnomAD2 exomes

AF:

0.0568

AC:

13832

AN:

243530

AF XY:

0.0555

show subpopulations

Gnomad AFR exome

AF:

0.00584

Gnomad AMR exome

AF:

0.184

Gnomad ASJ exome

AF:

0.0186

Gnomad EAS exome

AF:

0.000729

Gnomad FIN exome

AF:

0.0555

Gnomad NFE exome

AF:

0.0193

Gnomad OTH exome

AF:

0.0470

GnomAD4 exome

AF:

0.0316

AC:

45745

AN:

1448794

Hom.:

1883

Cov.:

AF XY:

0.0335

AC XY:

24086

AN XY:

718336

show subpopulations

African (AFR)

AF:

0.00509

AC:

168

AN:

33030

American (AMR)

AF:

0.180

AC:

7890

AN:

43916

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

497

AN:

25734

East Asian (EAS)

AF:

0.000508

AC:

AN:

39376

South Asian (SAS)

AF:

0.121

AC:

10283

AN:

85186

European-Finnish (FIN)

AF:

0.0566

AC:

3007

AN:

53112

Middle Eastern (MID)

AF:

0.0374

AC:

213

AN:

5692

European-Non Finnish (NFE)

AF:

0.0197

AC:

21752

AN:

1103008

Other (OTH)

AF:

0.0321

AC:

1915

AN:

59740

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

2092

4184

6277

8369

10461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

994

1988

2982

3976

4970

<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:

0.0326

AC:

4958

AN:

152120

Hom.:

245

Cov.:

AF XY:

0.0385

AC XY:

2864

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00657

AC:

273

AN:

41536

American (AMR)

AF:

0.131

AC:

1996

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.0170

AC:

AN:

3468

East Asian (EAS)

AF:

0.00155

AC:

AN:

5148

South Asian (SAS)

AF:

0.125

AC:

600

AN:

4814

European-Finnish (FIN)

AF:

0.0567

AC:

601

AN:

10604

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0194

AC:

1318

AN:

67976

Other (OTH)

AF:

0.0284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

224

448

672

896

1120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<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:

0.0224

Hom.:

295

Bravo

AF:

0.0340

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0195

AC:

ESP6500AA

AF:

0.00710

AC:

ESP6500EA

AF:

0.0190

AC:

158

ExAC

AF:

0.0498

AC:

6026

Asia WGS

AF:

0.0580

AC:

201

AN:

3478

EpiCase

AF:

0.0192

EpiControl

AF:

0.0180

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (10)

Autosomal recessive limb-girdle muscular dystrophy type 2J (2)

Early-onset myopathy with fatal cardiomyopathy (2)

Myopathy, myofibrillar, 9, with early respiratory failure (2)

Tibial muscular dystrophy (2)

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)

Cardiovascular phenotype (1)

Dilated cardiomyopathy 1G (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.2

PhyloP100

6.5

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.1

REVEL

Benign

0.20

Sift

Benign

0.55

Polyphen

0.81

Vest4

0.14

MPC

0.14

ClinPred

0.016

GERP RS

6.0

Mutation Taster

=77/23

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over