chr2-178549276-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4BP6_Moderate

The NM_001267550.2(TTN):c.92350G>T(p.Gly30784Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G30784R) has been classified as Uncertain significance.

Frequency

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

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.47

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:

ENSG00000270277 (HGNC:):

ENSG00000270277 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.40658355).

BP6

Variant 2-178549276-C-A is Benign according to our data. Variant chr2-178549276-C-A is described in CliVar as Likely_benign. Clinvar id is 1753976.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178549276-C-A is described in CliVar as Likely_benign. Clinvar id is 1753976.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178549276-C-A is described in CliVar as Likely_benign. Clinvar id is 1753976.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178549276-C-A is described in CliVar as Likely_benign. Clinvar id is 1753976.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178549276-C-A is described in CliVar as Likely_benign. Clinvar id is 1753976.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178549276-C-A is described in CliVar as Likely_benign. Clinvar id is 1753976.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178549276-C-A is described in CliVar as Likely_benign. Clinvar id is 1753976.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178549276-C-A is described in CliVar as Likely_benign. Clinvar id is 1753976.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178549276-C-A is described in CliVar as Likely_benign. Clinvar id is 1753976.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178549276-C-A is described in CliVar as Likely_benign. Clinvar id is 1753976.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178549276-C-A is described in CliVar as Likely_benign. Clinvar id is 1753976.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178549276-C-A is described in CliVar as Likely_benign. Clinvar id is 1753976.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178549276-C-A is described in CliVar as Likely_benign. Clinvar id is 1753976.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178549276-C-A is described in CliVar as Likely_benign. Clinvar id is 1753976.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178549276-C-A is described in CliVar as Likely_benign. Clinvar id is 1753976.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178549276-C-A is described in CliVar as Likely_benign. Clinvar id is 1753976.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178549276-C-A is described in CliVar as Likely_benign. Clinvar id is 1753976.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178549276-C-A is described in CliVar as Likely_benign. Clinvar id is 1753976.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178549276-C-A is described in CliVar as Likely_benign. Clinvar id is 1753976.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178549276-C-A is described in CliVar as Likely_benign. Clinvar id is 1753976.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.92350G>T	p.Gly30784Cys	missense_variant	Exon 339 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.92350G>T	p.Gly30784Cys	missense_variant	Exon 339 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000483

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

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:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.002339), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Benign:1

May 22, 2020

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.054

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.89

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;D;D;.;D;D;D

M_CAP

Benign

0.039

MetaRNN

Benign

0.41

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.40

MutationAssessor

Pathogenic

4.1

.;.;.;H;.;.;H

PhyloP100

2.5

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.3

D;D;.;.;D;D;.

REVEL

Uncertain

0.45

Sift

Uncertain

0.0030

D;D;.;.;D;D;.

Polyphen

1.0

.;.;.;D;.;.;D

Vest4

0.56

MutPred

0.64

.;.;.;Loss of disorder (P = 0.0526);.;.;Loss of disorder (P = 0.0526);

MVP

0.58

MPC

0.45

ClinPred

0.66

GERP RS

4.8

Mutation Taster

=80/20

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

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over