2-178609719-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001267550.2(TTN):c.51704G>A(p.Arg17235Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000454 in 1,607,018 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. R17235W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3O:1

Conservation

PhyloP100: 3.40

Publications

4 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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023222744).

BP6

Variant 2-178609719-C-T is Benign according to our data. Variant chr2-178609719-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 202695.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.51704G>A	p.Arg17235Gln	missense_variant	Exon 272 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.51704G>A	p.Arg17235Gln	missense_variant	Exon 272 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.0000659

AC:

AN:

151854

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000974

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000163

AC:

AN:

244912

AF XY:

0.000121

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000641

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000951

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000433

AC:

AN:

1455046

Hom.:

Cov.:

AF XY:

0.0000263

AC XY:

AN XY:

722942

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33336

American (AMR)

AF:

0.000651

AC:

AN:

44566

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25766

East Asian (EAS)

AF:

0.000556

AC:

AN:

39566

South Asian (SAS)

AF:

0.0000468

AC:

AN:

85434

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00000542

AC:

AN:

1107408

Other (OTH)

AF:

0.0000333

AC:

AN:

60080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.0000658

AC:

AN:

151972

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74248

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41494

American (AMR)

AF:

0.0000656

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.000977

AC:

AN:

5120

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67922

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.000174

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:1Other:1

Dec 20, 2012

GeneDx

Significance:not provided

Review Status:no classification provided

Collection Method:clinical testing

- -

May 17, 2023

Revvity Omics, Revvity

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Jan 16, 2024

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.44000G>A (p.Arg14667Gln) results in a conservative amino acid change located in the A band region of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 244912 control chromosomes (gnomAD). c.44000G>A has been reported in the literature in at-least one individual affected with Dilated cardiomyopathy (example: Zhang_2020). This report does not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Type 2J. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32041989). ClinVar contains an entry for this variant (Variation ID: 202695). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

Jun 11, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

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

Benign

0.18

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

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

M_CAP

Benign

0.023

MetaRNN

Benign

0.023

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

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

.;.;.;L;.;.;L

PhyloP100

3.4

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.7

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

REVEL

Benign

0.096

Sift

Benign

0.092

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

Polyphen

0.76

.;.;.;P;.;.;P

Vest4

0.30

MutPred

0.23

.;.;.;Loss of phosphorylation at S15593 (P = 0.1101);.;.;Loss of phosphorylation at S15593 (P = 0.1101);

MVP

0.14

MPC

0.14

ClinPred

0.076

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=92/8

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