rs184412722

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001267550.2(TTN):c.18824A>G(p.Asn6275Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00223 in 1,612,842 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 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 0.0018 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 47 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:22

Conservation

PhyloP100: 6.26

Publications

8 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005814582).

BP6

Variant 2-178729332-T-C is Benign according to our data. Variant chr2-178729332-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46646. Variant chr2-178729332-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46646. Variant chr2-178729332-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46646. Variant chr2-178729332-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46646. Variant chr2-178729332-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46646. Variant chr2-178729332-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46646. Variant chr2-178729332-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46646. Variant chr2-178729332-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46646. Variant chr2-178729332-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46646. Variant chr2-178729332-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46646. Variant chr2-178729332-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46646. Variant chr2-178729332-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46646. Variant chr2-178729332-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46646. Variant chr2-178729332-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46646. Variant chr2-178729332-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46646. Variant chr2-178729332-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46646. Variant chr2-178729332-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46646. Variant chr2-178729332-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46646. Variant chr2-178729332-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46646. Variant chr2-178729332-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46646.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00183 (279/152276) while in subpopulation SAS AF = 0.0244 (118/4828). AF 95% confidence interval is 0.0209. There are 6 homozygotes in GnomAd4. There are 162 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.18824A>G	p.Asn6275Ser	missense_variant	Exon 64 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.18824A>G	p.Asn6275Ser	missense_variant	Exon 64 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.00181

AC:

276

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0238

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00169

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00383

AC:

950

AN:

247794

AF XY:

0.00490

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.000784

Gnomad ASJ exome

AF:

0.000899

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00184

Gnomad OTH exome

AF:

0.00366

GnomAD4 exome

AF:

0.00227

AC:

3314

AN:

1460566

Hom.:

Cov.:

AF XY:

0.00291

AC XY:

2111

AN XY:

726384

show subpopulations

African (AFR)

AF:

0.000419

AC:

AN:

33434

American (AMR)

AF:

0.000716

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.000843

AC:

AN:

26100

East Asian (EAS)

AF:

0.000176

AC:

AN:

39670

South Asian (SAS)

AF:

0.0214

AC:

1847

AN:

86200

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00417

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00107

AC:

1185

AN:

1111024

Other (OTH)

AF:

0.00297

AC:

179

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

190

380

569

759

949

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.00183

AC:

279

AN:

152276

Hom.:

Cov.:

AF XY:

0.00218

AC XY:

162

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41572

American (AMR)

AF:

0.00183

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.0244

AC:

118

AN:

4828

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00169

AC:

115

AN:

68014

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.00163

Hom.:

Bravo

AF:

0.00105

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000530

AC:

ESP6500EA

AF:

0.00194

AC:

ExAC

AF:

0.00441

AC:

533

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.00267

EpiControl

AF:

0.00273

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:22

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:8

Feb 25, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Asn5031Ser in exon 61 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 2.4% (391/16028) of South Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs184412722). -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 01, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2016

GeneDx

Significance: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. -

Nov 05, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2020

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:6

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TTN: BP4, BS1, BS2 -

Mar 17, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1G

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiomyopathy

Benign:1

May 30, 2019

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Early-onset myopathy with fatal cardiomyopathy

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Tibial muscular dystrophy

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Myopathy, myofibrillar, 9, with early respiratory failure

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Primary dilated cardiomyopathy

Benign:1

Feb 28, 2017

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.94

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

T;D;.;D

MetaRNN

Benign

0.0058

T;T;T;T

MetaSVM

Benign

-0.56

PhyloP100

6.3

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.3

N;.;.;.

REVEL

Benign

0.29

Sift

Benign

0.075

T;.;.;.

Polyphen

0.36

.;.;B;B

Vest4

0.42

MVP

0.17

MPC

0.089

ClinPred

0.027

GERP RS

5.9

Mutation Taster

=48/52

disease causing

(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