2-178713381-TACAAAACAAAACAAA-TACAAAACAAAACAAAACAAAACAAAACAAAACAAAACAAAACAAA

Variant names:

• chr2-178713381-T-TACAAAACAAAACAAAACAAAACAAAACAAA
• rs71393436
• NM_001267550.2:c.26762-39_26762-10dupTTTGTTTTGTTTTGTTTTGTTTTGTTTTGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.26762-39_26762-10dupTTTGTTTTGTTTTGTTTTGTTTTGTTTTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000463 in 1,469,036 control chromosomes in the GnomAD database, including 5 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_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 0.00070 (0 hom., cov: 24)
  • Exomes 𝑓: 0.00044 (5 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.08
• 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 -16 ACMG points.

• BP6: Variant 2-178713381-T-TACAAAACAAAACAAAACAAAACAAAACAAA is Benign according to our data. Variant chr2-178713381-T-TACAAAACAAAACAAAACAAAACAAAACAAA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 413040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000702 (106/151012) while in subpopulation EAS AF = 0.0129 (65/5054). AF 95% confidence interval is 0.0104. There are 0 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.26762-39_26762-10dupTTTGTTTTGTTTTGTTTTGTTTTGTTTTGT		intron	N/A	NP_001254479.2
	TTN	NM_001256850.1		c.25811-39_25811-10dupTTTGTTTTGTTTTGTTTTGTTTTGTTTTGT		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.23030-39_23030-10dupTTTGTTTTGTTTTGTTTTGTTTTGTTTTGT		intron	N/A	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.26762-10_26762-9insTTTGTTTTGTTTTGTTTTGTTTTGTTTTGT		intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.26762-10_26762-9insTTTGTTTTGTTTTGTTTTGTTTTGTTTTGT		intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.26486-10_26486-9insTTTGTTTTGTTTTGTTTTGTTTTGTTTTGT		intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000702 AC: 106 AN: 150896 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00172

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0128

Gnomad SAS AF: 0.00127

Gnomad FIN AF: 0.0000954

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000885

Gnomad OTH AF: 0.000963

GnomAD2 exomes AF: 0.00121 AC: 122 AN: 100440 AF XY: 0.00127

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0118

Gnomad FIN exome AF: 0.000148

Gnomad NFE exome AF: 0.0000939

Gnomad OTH exome AF: 0.000356

GnomAD4 exome AF: 0.000436 AC: 574 AN: 1318024 Hom.: 5 Cov.: 33 AF XY: 0.000430 AC XY: 276 AN XY: 641892

African (AFR) AF: 0.00 AC: 0 AN: 28588

American (AMR) AF: 0.00123 AC: 27 AN: 22038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21172

East Asian (EAS) AF: 0.0135 AC: 463 AN: 34332

South Asian (SAS) AF: 0.000304 AC: 19 AN: 62458

European-Finnish (FIN) AF: 0.000384 AC: 18 AN: 46854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4006

European-Non Finnish (NFE) AF: 0.0000249 AC: 26 AN: 1044272

Other (OTH) AF: 0.000387 AC: 21 AN: 54304

GnomAD4 genome AF: 0.000702 AC: 106 AN: 151012 Hom.: 0 Cov.: 24 AF XY: 0.000733 AC XY: 54 AN XY: 73706

African (AFR) AF: 0.00 AC: 0 AN: 41028

American (AMR) AF: 0.00172 AC: 26 AN: 15152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0129 AC: 65 AN: 5054

South Asian (SAS) AF: 0.00127 AC: 6 AN: 4734

European-Finnish (FIN) AF: 0.0000954 AC: 1 AN: 10480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000885 AC: 6 AN: 67802

Other (OTH) AF: 0.000953 AC: 2 AN: 2098

Alfa AF: 0.0000447 Hom.: 211

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Nov 06, 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.23030-39_23030-10dup30 alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0012 in 100440 control chromosomes, predominantly at a frequency of 0.012 within the East Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 19-folds over the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.23030-39_23030-10dup30 in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Nov 05, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTN: BS1, BS2

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs71393436; hg19: chr2-179578108;