chr2-178614499-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BP6

The NM_001267550.2(TTN):c.49015C>T(p.Arg16339Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000534 in 1,610,362 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R16339Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 6.58

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.29161742).

BP6

Variant 2-178614499-G-A is Benign according to our data. Variant chr2-178614499-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238790. Variant chr2-178614499-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238790. Variant chr2-178614499-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238790. Variant chr2-178614499-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238790. Variant chr2-178614499-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238790. Variant chr2-178614499-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238790. Variant chr2-178614499-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238790. Variant chr2-178614499-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238790. Variant chr2-178614499-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238790. Variant chr2-178614499-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238790. Variant chr2-178614499-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238790. Variant chr2-178614499-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238790. Variant chr2-178614499-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238790. Variant chr2-178614499-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238790. Variant chr2-178614499-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238790. Variant chr2-178614499-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238790. Variant chr2-178614499-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238790. Variant chr2-178614499-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238790. Variant chr2-178614499-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238790. Variant chr2-178614499-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238790.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.49015C>T	p.Arg16339Trp	missense_variant	Exon 261 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.49015C>T	p.Arg16339Trp	missense_variant	Exon 261 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.000297

AC:

AN:

151700

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000895

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.0000589

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.0000730

AC:

AN:

246710

AF XY:

0.0000374

show subpopulations

Gnomad AFR exome

AF:

0.000841

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000565

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000268

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000281

AC:

AN:

1458662

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

725298

show subpopulations

African (AFR)

AF:

0.000869

AC:

AN:

33366

American (AMR)

AF:

0.0000449

AC:

AN:

44576

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26020

East Asian (EAS)

AF:

0.00

AC:

AN:

39432

South Asian (SAS)

AF:

0.00

AC:

AN:

85840

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53300

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1110156

Other (OTH)

AF:

0.0000498

AC:

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.000297

AC:

AN:

151700

Hom.:

Cov.:

AF XY:

0.000243

AC XY:

AN XY:

74050

show subpopulations

African (AFR)

AF:

0.000895

AC:

AN:

41330

American (AMR)

AF:

0.000197

AC:

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5126

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

67872

Other (OTH)

AF:

0.000480

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.000193

Hom.:

Bravo

AF:

0.000321

ESP6500AA

AF:

0.000763

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000910

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Nov 04, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 25, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2 -

not specified

Uncertain:1Benign:1

Mar 05, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jun 18, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Uncertain:1

Aug 14, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jul 10, 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

Pathogenic

0.65

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

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

M_CAP

Benign

0.036

MetaRNN

Benign

0.29

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

MetaSVM

Uncertain

0.28

MutationAssessor

Pathogenic

3.1

.;.;.;M;.;.;M

PhyloP100

6.6

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.9

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

REVEL

Uncertain

0.53

Sift

Uncertain

0.0030

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

Polyphen

1.0

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

Vest4

0.55

MVP

0.72

MPC

0.47

ClinPred

0.29

GERP RS

4.9

Mutation Taster

=70/30

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over