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

Variant names:

• chr2-178549978-A-T
• rs56145100
• NM_001267550.2:c.91852+8T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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: Splicing: ADA: 0.00002437
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: -0.221
• Publications: 6 publications found

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]

ENSG00000270277 (HGNC:):

ACMG classification

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
TTN	NM_001267550.2	c.91852+8T>A		splice_region_variant, intron_variant	Intron 337 of 362	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.91852+8T>A		splice_region_variant, intron_variant	Intron 337 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3076 AN: 152198 Hom.: 50 Cov.: 33

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

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

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

GnomAD4 genome AF: 0.0202 AC: 3073 AN: 152316 Hom.: 50 Cov.: 33 AF XY: 0.0207 AC XY: 1538 AN XY: 74472

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

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

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

Other links and lift over

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