rs139512154

Variant names:

• chr2-178650214-TTTTCCTCTTCAGGAGCAA-T
• rs139512154
• NM_001267550.2:c.39749_39766delTTGCTCCTGAAGAGGAAA

Your query was ambiguous. Multiple possible variants found:

• chr2-178650214-TTTTCCTCTTCAGGAGCAA-T
• chr2-178650214-TTTTCCTCTTCAGGAGCAA-TTTTCCTCTTCAGGAGCAATTTCCTCTTCAGGAGCAA

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.39749_39766delTTGCTCCTGAAGAGGAAA​(p.Ile13250_Glu13255del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,596,062 control chromosomes in the GnomAD database, including 290 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (120 hom., cov: 32)
  • Exomes 𝑓: 0.010 (170 hom.)
• Consequence: TTN NM_001267550.2 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.41
• Publications: 4 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001267550.2.
• BP6: Variant 2-178650214-TTTTCCTCTTCAGGAGCAA-T is Benign according to our data. Variant chr2-178650214-TTTTCCTCTTCAGGAGCAA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.39749_39766delTTGCTCCTGAAGAGGAAA	p.Ile13250_Glu13255del	disruptive_inframe_deletion	Exon 210 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.39749_39766delTTGCTCCTGAAGAGGAAA	p.Ile13250_Glu13255del	disruptive_inframe_deletion	Exon 210 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0281 AC: 4273 AN: 152052 Hom.: 120 Cov.: 32

Gnomad AFR AF: 0.0684

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0257

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00773

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.0180

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00919

Gnomad OTH AF: 0.0287

GnomAD2 exomes AF: 0.0105 AC: 2340 AN: 223830 AF XY: 0.0102

Gnomad AFR exome AF: 0.0460

Gnomad AMR exome AF: 0.00777

Gnomad ASJ exome AF: 0.00751

Gnomad EAS exome AF: 0.00448

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.00650

Gnomad OTH exome AF: 0.00951

GnomAD4 exome AF: 0.0102 AC: 14719 AN: 1443892 Hom.: 170 AF XY: 0.0104 AC XY: 7416 AN XY: 716464

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0564 AC: 1855 AN: 32894

American (AMR) AF: 0.0104 AC: 448 AN: 42994

Ashkenazi Jewish (ASJ) AF: 0.00934 AC: 240 AN: 25692

East Asian (EAS) AF: 0.00294 AC: 115 AN: 39066

South Asian (SAS) AF: 0.0170 AC: 1414 AN: 83338

European-Finnish (FIN) AF: 0.0147 AC: 770 AN: 52430

Middle Eastern (MID) AF: 0.0218 AC: 125 AN: 5740

European-Non Finnish (NFE) AF: 0.00806 AC: 8886 AN: 1102148

Other (OTH) AF: 0.0145 AC: 866 AN: 59590

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0281 AC: 4283 AN: 152170 Hom.: 120 Cov.: 32 AF XY: 0.0284 AC XY: 2112 AN XY: 74380

African (AFR) AF: 0.0685 AC: 2846 AN: 41532

American (AMR) AF: 0.0256 AC: 391 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3470

East Asian (EAS) AF: 0.00756 AC: 39 AN: 5160

South Asian (SAS) AF: 0.0174 AC: 84 AN: 4818

European-Finnish (FIN) AF: 0.0180 AC: 191 AN: 10616

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00919 AC: 625 AN: 67988

Other (OTH) AF: 0.0284 AC: 60 AN: 2112

Alfa AF: 0.00600 Hom.: 1

Bravo AF: 0.0297

Asia WGS AF: 0.0140 AC: 47 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Dec 23, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 29, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 27, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ile10816_Glu10821del in intron 164 of TTN: This variant is not expected to have clinical significance because it has been identified in 11.0% (21/192) of Luhya (Kenyan) chromosomes from a broad population by the 1000 Genomes project (dbSNP rs139512154).

Nov 18, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TTN c.32447_32464del18 (p.Ile10816_Glu10821del) results in an in-frame deletion that is predicted to remove six amino acids from the encoded protein. The variant allele was found at a frequency of 0.01 in 223830 control chromosomes in the gnomAD database, including 33 homozygotes. The observed variant frequency is approximately 17 fold the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is benign. Five ClinVar submitters (evaluation after 2014) have cited the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 14, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Nov 02, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 09, 2018

GeneDx

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 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiomyopathy Benign:1

Dec 17, 2015

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Mar 06, 2013

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: 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
PhyloP100		1.4
Mutation Taster		=183/17	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs139512154; hg19: chr2-179514941; COSMIC: COSV106496539; COSMIC: COSV106496539;