2-178713381-TACAAAACAAAACAAA-TACAAAACAAAACAAAACAAAACAAAACAAAACAAA

Position:

• chr2-178713381-TACAAAACAAAACAAA-TACAAAACAAAACAAAACAAAACAAAACAAAACAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.26762-10_26762-9insTTTGTTTTGTTTTGTTTTGT variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 151,004 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (12 hom., cov: 24)
  • Exomes 𝑓: 0.013 (154 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.08

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

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 2-178713381-T-TACAAAACAAAACAAAACAAA is Benign according to our data. Variant chr2-178713381-T-TACAAAACAAAACAAAACAAA is described in ClinVar as [Likely_benign]. Clinvar id is 167797.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 = 0.0104 (1575/151004) while in subpopulation NFE AF= 0.0151 (1025/67796). AF 95% confidence interval is 0.0144. There are 12 homozygotes in gnomad4. There are 722 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.26762-10_26762-9insTTTGTTTTGTTTTGTTTTGT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000589042.5	NP_001254479.2
LOC124906100	XR_007087318.1	n.2186-361_2186-342dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.26762-10_26762-9insTTTGTTTTGTTTTGTTTTGT		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.503-21111_503-21092dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1576 AN: 150888 Hom.: 12 Cov.: 24

Gnomad AFR AF: 0.00259

Gnomad AMI AF: 0.0243

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.0116

Gnomad SAS AF: 0.00127

Gnomad FIN AF: 0.00849

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.0116

GnomAD3 exomes AF: 0.00890 AC: 894 AN: 100440 Hom.: 10 AF XY: 0.00900 AC XY: 459 AN XY: 51018

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.0160

Gnomad ASJ exome AF: 0.00287

Gnomad EAS exome AF: 0.0130

Gnomad SAS exome AF: 0.000529

Gnomad FIN exome AF: 0.00925

Gnomad NFE exome AF: 0.00901

Gnomad OTH exome AF: 0.0149

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0127 AC: 16752 AN: 1317468 Hom.: 154 Cov.: 33 AF XY: 0.0126 AC XY: 8068 AN XY: 641600

Gnomad4 AFR exome AF: 0.00185

Gnomad4 AMR exome AF: 0.0150

Gnomad4 ASJ exome AF: 0.00751

Gnomad4 EAS exome AF: 0.0163

Gnomad4 SAS exome AF: 0.00114

Gnomad4 FIN exome AF: 0.0105

Gnomad4 NFE exome AF: 0.0139

Gnomad4 OTH exome AF: 0.0104

GnomAD4 genome AF: 0.0104 AC: 1575 AN: 151004 Hom.: 12 Cov.: 24 AF XY: 0.00980 AC XY: 722 AN XY: 73696

Gnomad4 AFR AF: 0.00258

Gnomad4 AMR AF: 0.0133

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.0117

Gnomad4 SAS AF: 0.00106

Gnomad4 FIN AF: 0.00849

Gnomad4 NFE AF: 0.0151

Gnomad4 OTH AF: 0.0115

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 04, 2015	c.23030-29_23030-10dup in intron 89 of TTN: This variant is part of a 5 bp repea t (TTTGT) and adds 4 repeat units to 6 present in the reference sequence. It is not expected to have clinical significance because it has been identified in 1.5 % (25/1672) of Finnish chromosomes and 0.7% (59/8302) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s71393436). -
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	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 04, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 19, 2015	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	TTN: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Mar 22, 2016

- -

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: rs71393436; hg19: chr2-179578108;