2-178537671-A-G

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.99536T>C(p.Val33179Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,613,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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. V33179D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.35

Publications

2 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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.074160516).

BP6

Variant 2-178537671-A-G is Benign according to our data. Variant chr2-178537671-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500742. Variant chr2-178537671-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500742. Variant chr2-178537671-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500742. Variant chr2-178537671-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500742. Variant chr2-178537671-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500742. Variant chr2-178537671-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500742. Variant chr2-178537671-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500742. Variant chr2-178537671-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500742. Variant chr2-178537671-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500742. Variant chr2-178537671-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500742. Variant chr2-178537671-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500742. Variant chr2-178537671-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500742. Variant chr2-178537671-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500742. Variant chr2-178537671-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500742. Variant chr2-178537671-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500742. Variant chr2-178537671-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500742. Variant chr2-178537671-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500742. Variant chr2-178537671-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500742. Variant chr2-178537671-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500742. Variant chr2-178537671-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500742.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.99536T>C	p.Val33179Ala	missense_variant	Exon 355 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.99536T>C	p.Val33179Ala	missense_variant	Exon 355 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000643

AC:

AN:

248956

AF XY:

0.0000518

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1461534

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727050

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33458

American (AMR)

AF:

0.000179

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39688

South Asian (SAS)

AF:

0.000197

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111780

Other (OTH)

AF:

0.0000828

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.0000197

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41420

American (AMR)

AF:

0.0000656

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

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:

0.0000434

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000579

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jun 15, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 06, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Nov 25, 2019

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TTN c.91832T>C (p.Val30611Ala) results in a non-conservative amino acid change located in the A-band of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 248956 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Cardiomyopathy (6.4e-05 vs 0.00063), allowing no conclusion about variant significance. c.91832T>C has been reported in the literature in an individual affected with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). The patient also carried two DSG2 variants, c.217-1G>T and p.F531C. Authors suggest that the F531C variant is the main reason for the ARVC/D with more severe phenotypes being presented due to the co-occurrence with the DSG2 splice variant (Lin_2018). A ClinVar submission (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.90

Eigen

Benign

-0.0012

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.82

T;T;T;.;T;T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.074

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

MetaSVM

Benign

-0.89

MutationAssessor

Benign

-0.32

.;.;.;N;.;.;N

PhyloP100

7.3

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.9

N;N;.;.;N;N;.

REVEL

Benign

0.23

Sift

Benign

0.61

T;T;.;.;T;T;.

Polyphen

0.0010

.;.;.;B;.;.;B

Vest4

0.47

MutPred

0.51

.;.;.;Loss of stability (P = 0.0568);.;.;Loss of stability (P = 0.0568);

MVP

0.38

MPC

0.10

ClinPred

0.080

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=71/29

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