dbSNP rs13388274: TTN:c.8902+14T>A (chr2-178769665-A-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001267550.2(TTN):c.8902+14T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 993,936 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 6)

Exomes 𝑓: 0.0022 ( 20 hom. )

Consequence

TTN
NM_001267550.2 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:12

Conservation

PhyloP100: -0.162

Publications

3 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 2-178769665-A-T is Benign according to our data. Variant chr2-178769665-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 137827.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0017 (109/64022) while in subpopulation EAS AF = 0.0333 (30/902). AF 95% confidence interval is 0.0239. There are 1 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 6. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 20 AD,AR gene

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	Effect	Exon Rank	Protein	UniProt
TTN	NM_001267550.2	MANE Select	c.8902+14T>A	intron	N/A	NP_001254479.2	Q8WZ42-12
TTN	NM_001256850.1		c.8902+14T>A	intron	N/A	NP_001243779.1	Q8WZ42-1
TTN	NM_133378.4		c.8902+14T>A	intron	N/A	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TTN	ENST00000589042.5	TSL:5 MANE Select	c.8902+14T>A	intron	N/A	ENSP00000467141.1	Q8WZ42-12
TTN	ENST00000446966.2	TSL:1	c.8902+14T>A	intron	N/A	ENSP00000408004.2	A0A1B0GXE3
TTN	ENST00000436599.2	TSL:1	c.8626+14T>A	intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes

AF:

0.00169

AC:

108

AN:

63966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00395

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000442

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0333

Gnomad SAS

AF:

0.00291

Gnomad FIN

AF:

0.000198

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000285

Gnomad OTH

AF:

0.00113

GnomAD2 exomes

AF:

0.0237

AC:

4653

AN:

196464

AF XY:

0.0241

show subpopulations

Gnomad AFR exome

AF:

0.0381

Gnomad AMR exome

AF:

0.0142

Gnomad ASJ exome

AF:

0.00707

Gnomad EAS exome

AF:

0.0903

Gnomad FIN exome

AF:

0.0132

Gnomad NFE exome

AF:

0.0213

Gnomad OTH exome

AF:

0.0133

GnomAD4 exome

AF:

0.00221

AC:

2059

AN:

929914

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

1025

AN XY:

466546

show subpopulations

African (AFR)

AF:

0.00592

AC:

102

AN:

17244

American (AMR)

AF:

0.000930

AC:

AN:

26896

Ashkenazi Jewish (ASJ)

AF:

0.000439

AC:

AN:

18232

East Asian (EAS)

AF:

0.0399

AC:

459

AN:

11500

South Asian (SAS)

AF:

0.00565

AC:

292

AN:

51712

European-Finnish (FIN)

AF:

0.000530

AC:

AN:

41516

Middle Eastern (MID)

AF:

0.00252

AC:

AN:

3174

European-Non Finnish (NFE)

AF:

0.00149

AC:

1072

AN:

721822

Other (OTH)

AF:

0.00188

AC:

AN:

37818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

136

204

272

340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.00170

AC:

109

AN:

64022

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

AN XY:

31322

show subpopulations

African (AFR)

AF:

0.00394

AC:

AN:

14988

American (AMR)

AF:

0.000441

AC:

AN:

6802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1682

East Asian (EAS)

AF:

0.0333

AC:

AN:

902

South Asian (SAS)

AF:

0.00290

AC:

AN:

1726

European-Finnish (FIN)

AF:

0.000198

AC:

AN:

5046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

126

European-Non Finnish (NFE)

AF:

0.000285

AC:

AN:

31616

Other (OTH)

AF:

0.00226

AC:

AN:

886

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00269

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (4)

Atrial fibrillation;C0018802:Congestive heart failure;C0042514:Ventricular tachycardia (1)

Autosomal recessive limb-girdle muscular dystrophy type 2J (1)

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

Dilated cardiomyopathy 1G (1)

Early-onset myopathy with fatal cardiomyopathy (1)

Myopathy, myofibrillar, 9, with early respiratory failure (1)

Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.3

(source)

DANN

Benign

0.60

PhyloP100

-0.16

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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