NM_001267550.2:c.91852+8T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001267550.2(TTN):​c.91852+8T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0228 in 1,596,054 control chromosomes in the GnomAD database, including 514 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 50 hom., cov: 33)
Exomes 𝑓: 0.023 ( 464 hom. )

Consequence

TTN
NM_001267550.2 splice_region, intron

Scores

2
Splicing: ADA: 0.00002437
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23

Conservation

PhyloP100: -0.221

Publications

6 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-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]

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP6
Variant 2-178549978-A-T is Benign according to our data. Variant chr2-178549978-A-T is described in CliVar as Benign/Likely_benign. Clinvar id is 47515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178549978-A-T is described in CliVar as Benign/Likely_benign. Clinvar id is 47515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178549978-A-T is described in CliVar as Benign/Likely_benign. Clinvar id is 47515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178549978-A-T is described in CliVar as Benign/Likely_benign. Clinvar id is 47515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178549978-A-T is described in CliVar as Benign/Likely_benign. Clinvar id is 47515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178549978-A-T is described in CliVar as Benign/Likely_benign. Clinvar id is 47515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178549978-A-T is described in CliVar as Benign/Likely_benign. Clinvar id is 47515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178549978-A-T is described in CliVar as Benign/Likely_benign. Clinvar id is 47515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178549978-A-T is described in CliVar as Benign/Likely_benign. Clinvar id is 47515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178549978-A-T is described in CliVar as Benign/Likely_benign. Clinvar id is 47515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178549978-A-T is described in CliVar as Benign/Likely_benign. Clinvar id is 47515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178549978-A-T is described in CliVar as Benign/Likely_benign. Clinvar id is 47515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178549978-A-T is described in CliVar as Benign/Likely_benign. Clinvar id is 47515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178549978-A-T is described in CliVar as Benign/Likely_benign. Clinvar id is 47515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178549978-A-T is described in CliVar as Benign/Likely_benign. Clinvar id is 47515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178549978-A-T is described in CliVar as Benign/Likely_benign. Clinvar id is 47515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178549978-A-T is described in CliVar as Benign/Likely_benign. Clinvar id is 47515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178549978-A-T is described in CliVar as Benign/Likely_benign. Clinvar id is 47515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178549978-A-T is described in CliVar as Benign/Likely_benign. Clinvar id is 47515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178549978-A-T is described in CliVar as Benign/Likely_benign. Clinvar id is 47515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0556 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.91852+8T>A splice_region_variant, intron_variant Intron 337 of 362 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.91852+8T>A splice_region_variant, intron_variant Intron 337 of 362 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.0202
AC:
3076
AN:
152198
Hom.:
50
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00451
Gnomad AMI
AF:
0.0307
Gnomad AMR
AF:
0.0217
Gnomad ASJ
AF:
0.0190
Gnomad EAS
AF:
0.0610
Gnomad SAS
AF:
0.00807
Gnomad FIN
AF:
0.0447
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.0234
Gnomad OTH
AF:
0.0191
GnomAD2 exomes
AF:
0.0261
AC:
6222
AN:
238298
AF XY:
0.0248
show subpopulations
Gnomad AFR exome
AF:
0.00464
Gnomad AMR exome
AF:
0.0338
Gnomad ASJ exome
AF:
0.0142
Gnomad EAS exome
AF:
0.0616
Gnomad FIN exome
AF:
0.0471
Gnomad NFE exome
AF:
0.0233
Gnomad OTH exome
AF:
0.0263
GnomAD4 exome
AF:
0.0231
AC:
33338
AN:
1443738
Hom.:
464
Cov.:
32
AF XY:
0.0227
AC XY:
16260
AN XY:
715492
show subpopulations
African (AFR)
AF:
0.00397
AC:
130
AN:
32776
American (AMR)
AF:
0.0317
AC:
1369
AN:
43206
Ashkenazi Jewish (ASJ)
AF:
0.0142
AC:
359
AN:
25352
East Asian (EAS)
AF:
0.0615
AC:
2421
AN:
39388
South Asian (SAS)
AF:
0.00656
AC:
550
AN:
83780
European-Finnish (FIN)
AF:
0.0483
AC:
2555
AN:
52894
Middle Eastern (MID)
AF:
0.00968
AC:
55
AN:
5680
European-Non Finnish (NFE)
AF:
0.0223
AC:
24606
AN:
1101190
Other (OTH)
AF:
0.0217
AC:
1293
AN:
59472
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.491
Heterozygous variant carriers
0
1829
3658
5487
7316
9145
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
980
1960
2940
3920
4900
<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:
0.0202
AC:
3073
AN:
152316
Hom.:
50
Cov.:
33
AF XY:
0.0207
AC XY:
1538
AN XY:
74472
show subpopulations
African (AFR)
AF:
0.00450
AC:
187
AN:
41574
American (AMR)
AF:
0.0217
AC:
332
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
0.0190
AC:
66
AN:
3470
East Asian (EAS)
AF:
0.0611
AC:
317
AN:
5186
South Asian (SAS)
AF:
0.00745
AC:
36
AN:
4830
European-Finnish (FIN)
AF:
0.0447
AC:
475
AN:
10616
Middle Eastern (MID)
AF:
0.00680
AC:
2
AN:
294
European-Non Finnish (NFE)
AF:
0.0234
AC:
1590
AN:
68030
Other (OTH)
AF:
0.0189
AC:
40
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.499
Heterozygous variant carriers
0
157
314
470
627
784
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
36
72
108
144
180
<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:
0.0200
Hom.:
10
Bravo
AF:
0.0185
Asia WGS
AF:
0.0280
AC:
96
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:23
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:10
Aug 15, 2013
Genetic Services Laboratory, University of Chicago
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 11, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Benign
Review Status:no assertion criteria provided
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

- -

Nov 14, 2011
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Nov 20, 2014
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 29, 2013
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

- -

not provided Benign:3
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jan 28, 2019
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:2
Sep 10, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 12, 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. -

Early-onset myopathy with fatal cardiomyopathy Benign:2
Jan 12, 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. -

Sep 10, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Tibial muscular dystrophy Benign:2
Jan 12, 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. -

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:2
Sep 10, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 12, 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. -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dilated cardiomyopathy 1G Benign:1
Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.80
CADD
Benign
6.9
DANN
Benign
0.73
PhyloP100
-0.22
Mutation Taster
=100/0
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000024
dbscSNV1_RF
Benign
0.11
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

Other links and lift over

dbSNP: rs56145100; hg19: chr2-179414705; COSMIC: COSV60085025; COSMIC: COSV60085025; API