rs72646883

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_001267550.2(TTN):c.69412+10G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000351 in 1,607,940 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 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

TTN
NM_001267550.2 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.124

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:

ENSG00000271011 (HGNC:):

ENSG00000271011 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 2-178576913-C-G is Benign according to our data. Variant chr2-178576913-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00181 (275/152216) while in subpopulation AFR AF = 0.00599 (249/41564). AF 95% confidence interval is 0.00538. There are 0 homozygotes in GnomAd4. There are 124 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TTN	NM_001267550.2	MANE Select	c.69412+10G>C	intron	N/A	NP_001254479.2
TTN	NM_001256850.1		c.64489+10G>C	intron	N/A	NP_001243779.1
TTN	NM_133378.4		c.61708+10G>C	intron	N/A	NP_596869.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TTN	ENST00000589042.5	TSL:5 MANE Select	c.69412+10G>C	intron	N/A	ENSP00000467141.1
TTN	ENST00000446966.2	TSL:1	c.69256+10G>C	intron	N/A	ENSP00000408004.2
TTN	ENST00000436599.2	TSL:1	c.69136+10G>C	intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes

AF:

0.00181

AC:

275

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00601

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

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:

0.0000294

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000458

AC:

112

AN:

244464

AF XY:

0.000392

show subpopulations

Gnomad AFR exome

AF:

0.00599

Gnomad AMR exome

AF:

0.000388

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000539

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.000199

AC:

290

AN:

1455724

Hom.:

Cov.:

AF XY:

0.000171

AC XY:

124

AN XY:

723798

show subpopulations

African (AFR)

AF:

0.00625

AC:

206

AN:

32968

American (AMR)

AF:

0.000505

AC:

AN:

43584

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25992

East Asian (EAS)

AF:

0.00

AC:

AN:

39626

South Asian (SAS)

AF:

0.00

AC:

AN:

85066

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53308

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1109364

Other (OTH)

AF:

0.000449

AC:

AN:

60086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.00181

AC:

275

AN:

152216

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

124

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00599

AC:

249

AN:

41564

American (AMR)

AF:

0.00144

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67974

Other (OTH)

AF:

0.000947

AC:

AN:

2112

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:

0.000940

Hom.:

Bravo

AF:

0.00239

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Sep 03, 2014

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 25, 2014

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.

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

Mar 19, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.61708+10G>C in Intron 273 of TTN: This variant is not expected to have clinica l significance because it is not located within the splice consensus sequence an d has been identified in 0.5% (17/3094) of African American chromosomes from a b road population by the NHLBI Exome Sequencing Project (http://evs.gs.washington. edu/EVS; dbSNP rs72646883).

Aug 19, 2023

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TTN-related disorder

Benign:1

Dec 04, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiomyopathy

Benign:1

Aug 11, 2016

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

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

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

8.8

(source)

DANN

Benign

0.77

PhyloP100

0.12

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over