rs200856239

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The ENST00000589042.5(TTN):c.28754A>G(p.Glu9585Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000349 in 1,575,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E9585K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

TTN
ENST00000589042.5 missense, splice_region

Scores

Splicing: ADA: 0.0008636

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 4.03

Publications

0 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:

LOC124906100 (HGNC:):

LOC124906100 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08452353).

BP6

Variant 2-178707813-T-C is Benign according to our data. Variant chr2-178707813-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 466982.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000589042.5. 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.28754A>G	p.Glu9585Gly	missense splice_region	Exon 100 of 363	NP_001254479.2
TTN	NM_001256850.1		c.27803A>G	p.Glu9268Gly	missense splice_region	Exon 98 of 313	NP_001243779.1
TTN	NM_133378.4		c.25022A>G	p.Glu8341Gly	missense splice_region	Exon 97 of 312	NP_596869.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTN	ENST00000589042.5	TSL:5 MANE Select	c.28754A>G	p.Glu9585Gly	missense splice_region	Exon 100 of 363	ENSP00000467141.1
TTN	ENST00000446966.2	TSL:1	c.28754A>G	p.Glu9585Gly	missense splice_region	Exon 100 of 361	ENSP00000408004.2
TTN	ENST00000436599.2	TSL:1	c.28478A>G	p.Glu9493Gly	missense splice_region	Exon 98 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000439

AC:

AN:

227618

AF XY:

0.0000243

show subpopulations

Gnomad AFR exome

AF:

0.000661

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000211

AC:

AN:

1423004

Hom.:

Cov.:

AF XY:

0.0000157

AC XY:

AN XY:

702574

show subpopulations

African (AFR)

AF:

0.000842

AC:

AN:

32070

American (AMR)

AF:

0.00

AC:

AN:

39580

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24542

East Asian (EAS)

AF:

0.00

AC:

AN:

39096

South Asian (SAS)

AF:

0.00

AC:

AN:

80910

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52702

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5600

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090006

Other (OTH)

AF:

0.0000513

AC:

AN:

58498

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000164

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.000579

AC:

AN:

41454

American (AMR)

AF:

0.0000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.0000739

Hom.:

Bravo

AF:

0.000178

ESP6500AA

AF:

0.000272

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000580

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

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

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.93

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.75

M_CAP

Benign

0.030

MetaRNN

Benign

0.085

MetaSVM

Benign

-0.96

PhyloP100

4.0

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.9

REVEL

Benign

0.13

Sift

Uncertain

0.027

Polyphen

0.52

Vest4

0.25

MVP

0.21

MPC

0.15

ClinPred

0.11

GERP RS

4.2

Mutation Taster

=47/53

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00086

dbscSNV1_RF

Benign

0.020

SpliceAI score (max)

0.080

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over