2-178615436-T-C

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.48509A>G(p.Asn16170Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000478 in 1,612,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/20 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. N16170T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.08

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05341935).

BP6

Variant 2-178615436-T-C is Benign according to our data. Variant chr2-178615436-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202667. Variant chr2-178615436-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202667. Variant chr2-178615436-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202667. Variant chr2-178615436-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202667. Variant chr2-178615436-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202667. Variant chr2-178615436-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202667. Variant chr2-178615436-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202667. Variant chr2-178615436-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202667. Variant chr2-178615436-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202667. Variant chr2-178615436-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202667. Variant chr2-178615436-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202667. Variant chr2-178615436-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202667. Variant chr2-178615436-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202667. Variant chr2-178615436-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202667. Variant chr2-178615436-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202667. Variant chr2-178615436-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202667. Variant chr2-178615436-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202667. Variant chr2-178615436-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202667. Variant chr2-178615436-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202667. Variant chr2-178615436-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 202667.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.48509A>G	p.Asn16170Ser	missense_variant	Exon 259 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.48509A>G	p.Asn16170Ser	missense_variant	Exon 259 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000821

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

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

GnomAD2 exomes

AF:

0.0000403

AC:

AN:

248274

AF XY:

0.00000742

show subpopulations

Gnomad AFR exome

AF:

0.000583

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000288

AC:

AN:

1460484

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

726538

show subpopulations

African (AFR)

AF:

0.000779

AC:

AN:

33388

American (AMR)

AF:

0.0000447

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39644

South Asian (SAS)

AF:

0.00

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00000720

AC:

AN:

1111078

Other (OTH)

AF:

0.0000663

AC:

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.000230

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.000818

AC:

AN:

41558

American (AMR)

AF:

0.0000656

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5120

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67906

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.0000773

Hom.:

Bravo

AF:

0.000219

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jun 26, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 08, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

May 07, 2022

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

Dec 17, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

Nov 15, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Oct 07, 2019

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

0.073

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.95

Eigen

Benign

-0.16

Eigen_PC

Benign

0.099

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.88

D;D;D;.;T;D;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.053

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

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.36

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

PhyloP100

3.1

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.6

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

REVEL

Benign

0.080

Sift

Benign

0.43

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

Polyphen

0.0

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

Vest4

0.30

MVP

0.099

MPC

0.067

ClinPred

0.033

GERP RS

6.0

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