chr2-178581719-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6_Very_StrongBP7

The NM_001267550.2(TTN):c.66549C>T(p.Asp22183Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000416 in 1,610,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

TTN
NM_001267550.2 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.225

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 -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 2-178581719-G-A is Benign according to our data. Variant chr2-178581719-G-A is described in CliVar as Likely_benign. Clinvar id is 467388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178581719-G-A is described in CliVar as Likely_benign. Clinvar id is 467388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178581719-G-A is described in CliVar as Likely_benign. Clinvar id is 467388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178581719-G-A is described in CliVar as Likely_benign. Clinvar id is 467388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178581719-G-A is described in CliVar as Likely_benign. Clinvar id is 467388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178581719-G-A is described in CliVar as Likely_benign. Clinvar id is 467388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178581719-G-A is described in CliVar as Likely_benign. Clinvar id is 467388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178581719-G-A is described in CliVar as Likely_benign. Clinvar id is 467388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178581719-G-A is described in CliVar as Likely_benign. Clinvar id is 467388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178581719-G-A is described in CliVar as Likely_benign. Clinvar id is 467388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178581719-G-A is described in CliVar as Likely_benign. Clinvar id is 467388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178581719-G-A is described in CliVar as Likely_benign. Clinvar id is 467388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178581719-G-A is described in CliVar as Likely_benign. Clinvar id is 467388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178581719-G-A is described in CliVar as Likely_benign. Clinvar id is 467388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178581719-G-A is described in CliVar as Likely_benign. Clinvar id is 467388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178581719-G-A is described in CliVar as Likely_benign. Clinvar id is 467388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178581719-G-A is described in CliVar as Likely_benign. Clinvar id is 467388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178581719-G-A is described in CliVar as Likely_benign. Clinvar id is 467388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178581719-G-A is described in CliVar as Likely_benign. Clinvar id is 467388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178581719-G-A is described in CliVar as Likely_benign. Clinvar id is 467388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.225 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.66549C>T	p.Asp22183Asp	synonymous_variant	Exon 316 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.66549C>T	p.Asp22183Asp	synonymous_variant	Exon 316 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000537

AC:

AN:

242026

AF XY:

0.0000305

show subpopulations

Gnomad AFR exome

AF:

0.000267

Gnomad AMR exome

AF:

0.000148

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000367

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000288

AC:

AN:

1457896

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

724988

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33396

American (AMR)

AF:

0.0000904

AC:

AN:

44272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26034

East Asian (EAS)

AF:

0.00

AC:

AN:

39276

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53172

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.0000234

AC:

AN:

1109994

Other (OTH)

AF:

0.0000332

AC:

AN:

60208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.000164

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.000409

AC:

AN:

41550

American (AMR)

AF:

0.000262

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

67974

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.000174

Hom.:

Bravo

AF:

0.000212

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TTN: BP4, BP7 -

Aug 01, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 18, 2023

Revvity Omics, Revvity

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

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

BP1;BP6 -

Jun 25, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Dec 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jul 20, 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

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.64

(source)

DANN

Benign

0.87

PhyloP100

0.23

Mutation Taster

=85/15

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