rs727503555

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_001267550.2(TTN):c.83820C>T(p.Asn27940Asn) variant causes a synonymous change. The variant allele was found at a frequency of 0.0000267 in 1,612,966 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000079 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

TTN
NM_001267550.2 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.79

Publications

0 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 2-178562312-G-A is Benign according to our data. Variant chr2-178562312-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 165792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.83820C>T	p.Asn27940Asn	synonymous_variant	Exon 326 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.83820C>T	p.Asn27940Asn	synonymous_variant	Exon 326 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000161

AC:

AN:

247688

AF XY:

0.0000298

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1460898

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726682

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33446

American (AMR)

AF:

0.0000224

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

1111570

Other (OTH)

AF:

0.00

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.0000789

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41404

American (AMR)

AF:

0.0000656

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68014

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.0000280

Hom.:

Bravo

AF:

0.0000378

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 22, 2021

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 27, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Asn25373Asn in exon 275 of TTN: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

May 17, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Sep 17, 2018

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

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.44

(source)

DANN

Benign

0.63

PhyloP100

3.8

Mutation Taster

=36/64

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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