2-178777914-G-A

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.4270C>T(p.Pro1424Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,613,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.27

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:

LOC101927055 (HGNC:):

LOC101927055 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=0.16945222).

BP6

Variant 2-178777914-G-A is Benign according to our data. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128. Variant chr2-178777914-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 203128.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.4270C>T	p.Pro1424Ser	missense_variant	Exon 25 of 363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7
TTN	NM_133379.5 link	c.4270C>T	p.Pro1424Ser	missense_variant	Exon 25 of 46	ENST00000360870.10	NP_596870.2	Q8WZ42-6Q7Z3B7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.4270C>T	p.Pro1424Ser	missense_variant	Exon 25 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7
TTN	ENST00000360870.10 link	c.4270C>T	p.Pro1424Ser	missense_variant	Exon 25 of 46	5	NM_133379.5	ENSP00000354117.4		Q8WZ42-6

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

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

GnomAD2 exomes

AF:

0.0000399

AC:

AN:

250552

AF XY:

0.0000443

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461636

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727120

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.000157

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000279

AC:

AN:

1111884

Other (OTH)

AF:

0.0000166

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

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:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.725

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:

0.00000756

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Sep 17, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 03, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

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

0.28

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.95

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

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

M_CAP

Benign

0.030

MetaRNN

Benign

0.17

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

MetaSVM

Uncertain

-0.26

PhyloP100

4.3

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.3

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

REVEL

Benign

0.17

Sift

Benign

0.42

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

Sift4G

Uncertain

0.014

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

Polyphen

0.80, 0.98

.;.;.;P;.;.;P;D

Vest4

0.24

MutPred

0.23

Gain of phosphorylation at P1424 (P = 6e-04);.;Gain of phosphorylation at P1424 (P = 6e-04);Gain of phosphorylation at P1424 (P = 6e-04);.;.;Gain of phosphorylation at P1424 (P = 6e-04);Gain of phosphorylation at P1424 (P = 6e-04);

MVP

0.32

MPC

0.11

ClinPred

0.058

GERP RS

5.5

Mutation Taster

=86/14

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