chr2-178752043-GA-G

Position:

• chr2-178752043-GA-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_133379.5(TTN):​c.10361-5del 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (33400 hom., cov: 0)
  • Exomes 𝑓: 0.45 (13505 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_133379.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:5
• Conservation: PhyloP100: 2.56

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 -16 ACMG points.

• BP6: Variant 2-178752043-GA-G is Benign according to our data. Variant chr2-178752043-GA-G is described in ClinVar as [Likely_benign]. Clinvar id is 47724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178752043-GA-G is described in Lovd as [Benign]. Variant chr2-178752043-GA-G is described in Lovd as [Benign]. Variant chr2-178752043-GA-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.11311+1080del		intron_variant		ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.10361-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000360870.10	NP_596870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000360870.10	c.10361-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_133379.5	ENSP00000354117
TTN	ENST00000589042.5	c.11311+1080del		intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.1224-4208del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.692 AC: 97487 AN: 140786 Hom.: 33390 Cov.: 0

Gnomad AFR AF: 0.762

Gnomad AMI AF: 0.808

Gnomad AMR AF: 0.645

Gnomad ASJ AF: 0.555

Gnomad EAS AF: 0.913

Gnomad SAS AF: 0.647

Gnomad FIN AF: 0.706

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.653

Gnomad OTH AF: 0.658

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.454 AC: 564297 AN: 1243988 Hom.: 13505 Cov.: 0 AF XY: 0.453 AC XY: 281815 AN XY: 622722

Gnomad4 AFR exome AF: 0.484

Gnomad4 AMR exome AF: 0.447

Gnomad4 ASJ exome AF: 0.404

Gnomad4 EAS exome AF: 0.506

Gnomad4 SAS exome AF: 0.439

Gnomad4 FIN exome AF: 0.470

Gnomad4 NFE exome AF: 0.453

Gnomad4 OTH exome AF: 0.453

GnomAD4 genome AF: 0.692 AC: 97520 AN: 140838 Hom.: 33400 Cov.: 0 AF XY: 0.693 AC XY: 47224 AN XY: 68180

Gnomad4 AFR AF: 0.762

Gnomad4 AMR AF: 0.645

Gnomad4 ASJ AF: 0.555

Gnomad4 EAS AF: 0.913

Gnomad4 SAS AF: 0.646

Gnomad4 FIN AF: 0.706

Gnomad4 NFE AF: 0.653

Gnomad4 OTH AF: 0.661

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 20, 2013	10361-5delT in intron 45 of TTN: This variant is not expected to have clinical s ignificance because it is located outside the conserved +/- 1, 2 region of the s plicing consensus sequence and as part of a polyT stretch. This variant has bee n reported in dbSNP (rs66641728) without frequency information. 10361-5delT in intron 45 of TTN (rs66641728; allele frequency = n/a) -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Dilated cardiomyopathy 1G Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Sep 26, 2015

- -

Hypertrophic cardiomyopathy 9 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Sep 26, 2015

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs58651353; hg19: chr2-179616770;