rs77483833

chr2-178535858-G-Achr2-178535858-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001267550.2(TTN):c.100766-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001820
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.467

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 2-178535858-G-A is Benign according to our data. Variant chr2-178535858-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 47631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.100766-9C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000589042.5
TTN-AS1	NR_038272.1	n.316+30G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.100766-9C>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.416+12222G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00 AC: 199 AN: 104304 Hom.: 0 Cov.: 30 FAILED QC

Gnomad AFR AF: 0.00161

Gnomad AMI AF: 0.00332

Gnomad AMR AF: 0.000908

Gnomad ASJ AF: 0.000754

Gnomad EAS AF: 0.000521

Gnomad SAS AF: 0.00170

Gnomad FIN AF: 0.00969

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00155

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0116 AC: 643 AN: 55198 Hom.: 0 AF XY: 0.0115 AC XY: 336 AN XY: 29178

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.00962

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.00803

Gnomad SAS exome AF: 0.0121

Gnomad FIN exome AF: 0.0190

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.00813

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00220 AC: 2489 AN: 1129796 Hom.: 0 Cov.: 27 AF XY: 0.00253 AC XY: 1403 AN XY: 553568

Gnomad4 AFR exome AF: 0.00396

Gnomad4 AMR exome AF: 0.00895

Gnomad4 ASJ exome AF: 0.00303

Gnomad4 EAS exome AF: 0.00344

Gnomad4 SAS exome AF: 0.00938

Gnomad4 FIN exome AF: 0.00579

Gnomad4 NFE exome AF: 0.00137

Gnomad4 OTH exome AF: 0.00163

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00192 AC: 200 AN: 104330 Hom.: 0 Cov.: 30 AF XY: 0.00207 AC XY: 103 AN XY: 49684

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.000907

Gnomad4 ASJ AF: 0.000754

Gnomad4 EAS AF: 0.000522

Gnomad4 SAS AF: 0.00171

Gnomad4 FIN AF: 0.00969

Gnomad4 NFE AF: 0.00155

Gnomad4 OTH AF: 0.000705

Alfa AF: 0.00196 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

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

Nov 22, 2011

93062-9C>T in intron 306 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 poly T stretch. -

Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 18, 2022

- -

Early-onset myopathy with fatal cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Tibial muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	18
Dann	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0018
dbscSNV1_RF	Benign	0.054
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: rs77483833; hg19: chr2-179400585;