chr2-178704657-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_ModerateBP6_Moderate

The NM_001267550.2(TTN):c.29815G>C(p.Glu9939Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,459,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.09

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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10026127).

BP6

Variant 2-178704657-C-G is Benign according to our data. Variant chr2-178704657-C-G is described in CliVar as Likely_benign. Clinvar id is 166126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178704657-C-G is described in CliVar as Likely_benign. Clinvar id is 166126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178704657-C-G is described in CliVar as Likely_benign. Clinvar id is 166126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178704657-C-G is described in CliVar as Likely_benign. Clinvar id is 166126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178704657-C-G is described in CliVar as Likely_benign. Clinvar id is 166126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178704657-C-G is described in CliVar as Likely_benign. Clinvar id is 166126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178704657-C-G is described in CliVar as Likely_benign. Clinvar id is 166126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178704657-C-G is described in CliVar as Likely_benign. Clinvar id is 166126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178704657-C-G is described in CliVar as Likely_benign. Clinvar id is 166126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178704657-C-G is described in CliVar as Likely_benign. Clinvar id is 166126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178704657-C-G is described in CliVar as Likely_benign. Clinvar id is 166126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178704657-C-G is described in CliVar as Likely_benign. Clinvar id is 166126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178704657-C-G is described in CliVar as Likely_benign. Clinvar id is 166126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178704657-C-G is described in CliVar as Likely_benign. Clinvar id is 166126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178704657-C-G is described in CliVar as Likely_benign. Clinvar id is 166126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178704657-C-G is described in CliVar as Likely_benign. Clinvar id is 166126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178704657-C-G is described in CliVar as Likely_benign. Clinvar id is 166126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178704657-C-G is described in CliVar as Likely_benign. Clinvar id is 166126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178704657-C-G is described in CliVar as Likely_benign. Clinvar id is 166126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178704657-C-G is described in CliVar as Likely_benign. Clinvar id is 166126.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.29815G>C	p.Glu9939Gln	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.29815G>C	p.Glu9939Gln	missense_variant	Exon 105 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000122

AC:

AN:

245018

AF XY:

0.0000150

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1459890

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726056

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.000116

AC:

AN:

86068

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53156

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110924

Other (OTH)

AF:

0.00

AC:

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.405

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

Cov.:

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Apr 03, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Glu8695Gln in exon 102 of TTN: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, 4 primates as well as multiple bird and fish species have a glutamine (Gln) at this position despite high nearby amino acid conservation. In addition, compu tational prediction tools do not suggest a high likelihood of impact to the prot ein. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.84

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.70

T;T;.;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Benign

-0.96

PhyloP100

3.1

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.82

N;.;.;.

REVEL

Benign

0.15

Sift

Benign

0.44

T;.;.;.

Polyphen

0.0030

.;.;B;B

Vest4

0.079

MutPred

0.38

.;.;Loss of disorder (P = 0.1092);Loss of disorder (P = 0.1092);

MVP

0.22

MPC

0.085

ClinPred

0.034

GERP RS

5.0

Mutation Taster

=93/7

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over