rs397517815

Positions:

• chr2-178747082-A-ATATCGCTCTAGAGTCTCTCCTGGGGGTGTGGAG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM4 BP6_Very_Strong BS1

The NM_133379.5(TTN):​c.15317_15318insCTCCACACCCCCAGGAGAGACTCTAGAGCGATA​(p.Thr5102_Glu5112dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 148,292 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Y5106Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (8 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_133379.5 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: 0.853

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_133379.5.
• BP6: Variant 2-178747082-A-ATATCGCTCTAGAGTCTCTCCTGGGGGTGTGGAG is Benign according to our data. Variant chr2-178747082-A-ATATCGCTCTAGAGTCTCTCCTGGGGGTGTGGAG is described in ClinVar as [Likely_benign]. Clinvar id is 47784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00259 (384/148292) while in subpopulation NFE AF= 0.00462 (308/66642). AF 95% confidence interval is 0.0042. There are 0 homozygotes in gnomad4. There are 169 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_133379.5	c.15317_15318insCTCCACACCCCCAGGAGAGACTCTAGAGCGATA	p.Thr5102_Glu5112dup	inframe_insertion	46/46	ENST00000360870.10
TTN	NM_001267550.2	c.11312-5162_11312-5161insCTCCACACCCCCAGGAGAGACTCTAGAGCGATA		intron_variant		ENST00000589042.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000360870.10	c.15317_15318insCTCCACACCCCCAGGAGAGACTCTAGAGCGATA	p.Thr5102_Glu5112dup	inframe_insertion	46/46	5	NM_133379.5
TTN	ENST00000589042.5	c.11312-5162_11312-5161insCTCCACACCCCCAGGAGAGACTCTAGAGCGATA		intron_variant		5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.1223+4117_1223+4149dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 384 AN: 148172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000501

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00201

Gnomad ASJ AF: 0.00117

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00174

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00462

Gnomad OTH AF: 0.00196

GnomAD3 exomes AF: 0.00270 AC: 673 AN: 249514 Hom.: 3 AF XY: 0.00261 AC XY: 353 AN XY: 134998

Gnomad AFR exome AF: 0.000749

Gnomad AMR exome AF: 0.000960

Gnomad ASJ exome AF: 0.000505

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000656

Gnomad FIN exome AF: 0.00186

Gnomad NFE exome AF: 0.00502

Gnomad OTH exome AF: 0.00248

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00312 AC: 4551 AN: 1458100 Hom.: 8 Cov.: 34 AF XY: 0.00306 AC XY: 2222 AN XY: 725458

Gnomad4 AFR exome AF: 0.000539

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.000500

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00169

Gnomad4 NFE exome AF: 0.00381

Gnomad4 OTH exome AF: 0.00246

GnomAD4 genome AF: 0.00259 AC: 384 AN: 148292 Hom.: 0 Cov.: 32 AF XY: 0.00233 AC XY: 169 AN XY: 72482

Gnomad4 AFR AF: 0.000499

Gnomad4 AMR AF: 0.00201

Gnomad4 ASJ AF: 0.00117

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00174

Gnomad4 NFE AF: 0.00462

Gnomad4 OTH AF: 0.00193

Alfa AF: 0.00296 Hom.: 0

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 27, 2016	p.Thr5102_Glu5112dup (T5102_E5112dup, c.15285_15317dup33:) in exon 46 of the TTN gene (NM_133379.3, alternate transcript). Seen in a patient in our center with LVNC and reduced systolic function. Given the location, lack of case data, and frequency in ExAC, we consider this variant a variant of uncertain significance, probably benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has not been reported in association with disease. Based on the genomic position (hg19 ) and https://cardiodb.org/titin/ it appears the variant is in the I-band distant from the A band. To date it appears that pathogenic variants in TTN are in the A band (or the I band near the A band). ExAC: 0.6% (376/66452) European chromosomes. -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	TTN: PM4, BS2 -

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 09, 2015	p.Thr5102_Glu5112dup in exon 45A of TTN: This variant is not expected to be clin ically significant because it has been identified in 0.6% (376/66452) European c hromosomes, including 2 homozygotes, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397517815) and in 1.1% (4/372) Caucasian control chromosomes tested by our laboratory (LMM unpublished data). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jan 17, 2017	- -

TTN-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2019

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;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397517815; hg19: chr2-179611809;