2-178527300-C-T

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.107688G>A(p.Pro35896Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000447 in 1,589,870 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 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

TTN
NM_001267550.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.314

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=-0.34).

BP6

Variant 2-178527300-C-T is Benign according to our data. Variant chr2-178527300-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 220650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178527300-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 220650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178527300-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 220650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178527300-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 220650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178527300-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 220650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178527300-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 220650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178527300-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 220650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178527300-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 220650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178527300-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 220650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178527300-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 220650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178527300-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 220650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178527300-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 220650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178527300-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 220650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178527300-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 220650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178527300-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 220650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178527300-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 220650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178527300-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 220650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178527300-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 220650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178527300-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 220650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178527300-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 220650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.314 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.107688G>A	p.Pro35896Pro	synonymous_variant	Exon 363 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.107688G>A	p.Pro35896Pro	synonymous_variant	Exon 363 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000121

AC:

AN:

231010

AF XY:

0.0000878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000326

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00129

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000376

Gnomad OTH exome

AF:

0.000182

GnomAD4 exome

AF:

0.0000396

AC:

AN:

1437706

Hom.:

Cov.:

AF XY:

0.0000365

AC XY:

AN XY:

712334

show subpopulations

African (AFR)

AF:

0.0000310

AC:

AN:

32280

American (AMR)

AF:

0.0000488

AC:

AN:

40956

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25114

East Asian (EAS)

AF:

0.000559

AC:

AN:

39348

South Asian (SAS)

AF:

0.0000242

AC:

AN:

82644

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52890

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5630

European-Non Finnish (NFE)

AF:

0.0000182

AC:

AN:

1099622

Other (OTH)

AF:

0.000169

AC:

AN:

59222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.0000920

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41500

American (AMR)

AF:

0.000131

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.0000850

Hom.:

Bravo

AF:

0.0000907

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Aug 03, 2017

GeneDx

Significance:Likely 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. -

Autosomal recessive limb-girdle muscular dystrophy type 2J

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: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

Jul 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Early-onset myopathy with fatal cardiomyopathy

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

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

Benign:1

Oct 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Sep 07, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Myopathy, myofibrillar, 9, with early respiratory failure

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tibial muscular dystrophy

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jul 24, 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

-0.34

CADD

Benign

0.12

(source)

DANN

Benign

0.80

PhyloP100

0.31

Mutation Taster

=77/23

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