2-178752043-GAAAA-GAA

Position:

• chr2-178752043-GAAAA-GAA

Variant summary

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

The NM_133379.5(TTN):​c.10361-6_10361-5del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,358,708 control chromosomes in the GnomAD database, including 2,092 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (580 hom., cov: 0)
  • Exomes 𝑓: 0.13 (1512 hom.)
• Consequence: TTN NM_133379.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.35

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-GAA-G is Benign according to our data. Variant chr2-178752043-GAA-G is described in ClinVar as [Likely_benign]. Clinvar id is 47725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178752043-GAA-G is described in Lovd as [Benign]. Variant chr2-178752043-GAA-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.11311+1079_11311+1080del		intron_variant		ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.10361-6_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.10361-6_10361-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_133379.5	ENSP00000354117
TTN	ENST00000589042.5	c.11311+1079_11311+1080del		intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.1224-4209_1224-4208del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0856 AC: 12065 AN: 140878 Hom.: 581 Cov.: 0

Gnomad AFR AF: 0.0264

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0700

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0589

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.132

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.0969

GnomAD4 exome AF: 0.135 AC: 163889 AN: 1217776 Hom.: 1512 AF XY: 0.134 AC XY: 81808 AN XY: 609084

Gnomad4 AFR exome AF: 0.0529

Gnomad4 AMR exome AF: 0.0810

Gnomad4 ASJ exome AF: 0.126

Gnomad4 EAS exome AF: 0.102

Gnomad4 SAS exome AF: 0.128

Gnomad4 FIN exome AF: 0.135

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.131

GnomAD4 genome AF: 0.0856 AC: 12068 AN: 140932 Hom.: 580 Cov.: 0 AF XY: 0.0860 AC XY: 5868 AN XY: 68224

Gnomad4 AFR AF: 0.0263

Gnomad4 AMR AF: 0.0699

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.0593

Gnomad4 SAS AF: 0.114

Gnomad4 FIN AF: 0.113

Gnomad4 NFE AF: 0.119

Gnomad4 OTH AF: 0.0964

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 27, 2011

10361-6_10361-5delTT in intron 45 of TTN: This variant is not expected to have c linical significance because it is located outside the conserved +/- 1, 2 region of the splicing consensus sequence and as part of a polyT stretch. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 13, 2019

This variant is associated with the following publications: (PMID: 28798025) -

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;