2-178698916-TAAAAAAAAA-TAAAAAAAA

Position:

• chr2-178698916-TAAAAAAAAA-TAAAAAAAA

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_001267550.2(TTN):​c.30683-3del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0042 (0 hom., cov: 30)
  • Exomes 𝑓: 0.28 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:7 O:1
• Conservation: PhyloP100: 0.401

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 Likely_benign. Variant got -1 ACMG points.

• BP6: Variant 2-178698916-TA-T is Benign according to our data. Variant chr2-178698916-TA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 332897.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=3, not_provided=1, Uncertain_significance=6}. Variant chr2-178698916-TA-T is described in Lovd as [Benign]. Variant chr2-178698916-TA-T is described in Lovd as [Benign]. Variant chr2-178698916-TA-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.30683-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000589042.5	NP_001254479.2
LOC124906100	XR_007087318.1	n.2186-14823del		intron_variant, non_coding_transcript_variant
LOC124907912	XR_007087321.1	n.7314+3480del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.30683-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.503-35573del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00 AC: 352 AN: 85014 Hom.: 0 Cov.: 30 FAILED QC

Gnomad AFR AF: 0.00172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00555

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00388

Gnomad SAS AF: 0.00206

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00428

Gnomad OTH AF: 0.00280

GnomAD3 exomes AF: 0.355 AC: 23344 AN: 65808 Hom.: 0 AF XY: 0.365 AC XY: 13063 AN XY: 35820

Gnomad AFR exome AF: 0.305

Gnomad AMR exome AF: 0.357

Gnomad ASJ exome AF: 0.400

Gnomad EAS exome AF: 0.354

Gnomad SAS exome AF: 0.402

Gnomad FIN exome AF: 0.350

Gnomad NFE exome AF: 0.338

Gnomad OTH exome AF: 0.363

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.282 AC: 278032 AN: 985106 Hom.: 0 Cov.: 0 AF XY: 0.285 AC XY: 138309 AN XY: 486012

Gnomad4 AFR exome AF: 0.319

Gnomad4 AMR exome AF: 0.309

Gnomad4 ASJ exome AF: 0.328

Gnomad4 EAS exome AF: 0.337

Gnomad4 SAS exome AF: 0.307

Gnomad4 FIN exome AF: 0.303

Gnomad4 NFE exome AF: 0.275

Gnomad4 OTH exome AF: 0.298

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00419 AC: 356 AN: 85034 Hom.: 0 Cov.: 30 AF XY: 0.00517 AC XY: 210 AN XY: 40594

Gnomad4 AFR AF: 0.00185

Gnomad4 AMR AF: 0.00554

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00390

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0128

Gnomad4 NFE AF: 0.00428

Gnomad4 OTH AF: 0.00371

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Apr 04, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Limb-girdle muscular dystrophy, recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Early-onset myopathy with fatal cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated Cardiomyopathy, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Myopathy, myofibrillar, 9, with early respiratory failure Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Tibial muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Dilated cardiomyopathy 1G Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 06, 2019

- -

Hypertrophic cardiomyopathy 2 Other:1

not provided, no classification provided

clinical testing

Institute of Human Genetics, University of Wuerzburg

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs368277751; hg19: chr2-179563643;