2-178713381-TACAAAACAAAACAAA-TACAAAACAAAACAAAACAAAACAAAACAAAACAAAACAAAACAAA

Position:

• chr2-178713381-TACAAAACAAAACAAA-TACAAAACAAAACAAAACAAAACAAAACAAAACAAAACAAAACAAA

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_26762-9insTTTGTTTTGTTTTGTTTTGTTTTGTTTTGT 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 0.000463 in 1,469,036 control chromosomes in the GnomAD database, including 5 homozygotes. 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• 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-TACAAAACAAAACAAAACAAAACAAAACAAA is Benign according to our data. Variant chr2-178713381-T-TACAAAACAAAACAAAACAAAACAAAACAAA is described in ClinVar as [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.26762-10_26762-9insTTTGTTTTGTTTTGTTTTGTTTTGTTTTGT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000589042.5	NP_001254479.2
LOC124906100	XR_007087318.1	n.2186-371_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_26762-9insTTTGTTTTGTTTTGTTTTGTTTTGTTTTGT		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.503-21121_503-21092dup		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes AF: 0.00121 AC: 122 AN: 100440 Hom.: 4 AF XY: 0.00127 AC XY: 65 AN XY: 51018

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 SAS exome AF: 0.000423

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0135

Gnomad4 SAS exome AF: 0.000304

Gnomad4 FIN exome AF: 0.000384

Gnomad4 NFE exome AF: 0.0000249

Gnomad4 OTH exome AF: 0.000387

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00172

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0129

Gnomad4 SAS AF: 0.00127

Gnomad4 FIN AF: 0.0000954

Gnomad4 NFE AF: 0.0000885

Gnomad4 OTH AF: 0.000953

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 06, 2019	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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	TTN: BS1, BS2 -

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 29, 2024

- -

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;