rs373651676

Variant names:

Variant summary

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

The NM_001267550.2(TTN):c.29762T>C(p.Ile9921Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000434 in 1,611,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I9921I) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 5.38

Publications

1 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=0.16969803).

BP6

Variant 2-178704710-A-G is Benign according to our data. Variant chr2-178704710-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202552. Variant chr2-178704710-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202552. Variant chr2-178704710-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202552. Variant chr2-178704710-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202552. Variant chr2-178704710-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202552. Variant chr2-178704710-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202552. Variant chr2-178704710-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202552. Variant chr2-178704710-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202552. Variant chr2-178704710-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202552. Variant chr2-178704710-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202552. Variant chr2-178704710-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202552. Variant chr2-178704710-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202552. Variant chr2-178704710-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202552. Variant chr2-178704710-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202552. Variant chr2-178704710-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202552. Variant chr2-178704710-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202552. Variant chr2-178704710-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202552. Variant chr2-178704710-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202552. Variant chr2-178704710-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202552. Variant chr2-178704710-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202552.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.29762T>C	p.Ile9921Thr	missense_variant	Exon 105 of 363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.29762T>C	p.Ile9921Thr	missense_variant	Exon 105 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000407

AC:

AN:

245790

AF XY:

0.0000450

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000807

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000466

AC:

AN:

1459146

Hom.:

Cov.:

AF XY:

0.0000427

AC XY:

AN XY:

725796

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44576

Ashkenazi Jewish (ASJ)

AF:

0.0000766

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51806

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000567

AC:

AN:

1111324

Other (OTH)

AF:

0.0000332

AC:

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.0000131

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000565

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.0000580

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:1

May 16, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Uncertain:1

May 31, 2017

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jun 03, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.93

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

T;D;.;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.17

T;T;T;T

MetaSVM

Benign

-0.99

PhyloP100

5.4

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-2.2

N;.;.;.

REVEL

Benign

0.17

Sift

Benign

0.24

T;.;.;.

Polyphen

0.42

.;.;B;B

Vest4

0.24

MVP

0.42

MPC

0.20

ClinPred

0.19

GERP RS

5.8

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over