chr2-178653611-T-TA

Variant names:

• chr2-178653611-T-TA
• rs1260372587
• NM_001267550.2:c.38626+9dupT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001267550.2(TTN):​c.38626+9dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., cov: 22)
  • Exomes 𝑓: 0.000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.844
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.38626+9dupT		intron_variant	Intron 196 of 362	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.38626+9_38626+10insT		intron_variant	Intron 196 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0000284 AC: 4 AN: 140924 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000107 AC: 10 AN: 935802 Hom.: 0 Cov.: 13 AF XY: 0.0000128 AC XY: 6 AN XY: 466960

African (AFR) AF: 0.0000873 AC: 2 AN: 22912

American (AMR) AF: 0.00 AC: 0 AN: 19544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16938

East Asian (EAS) AF: 0.00 AC: 0 AN: 33552

South Asian (SAS) AF: 0.000128 AC: 7 AN: 54476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2960

European-Non Finnish (NFE) AF: 0.00000140 AC: 1 AN: 713058

Other (OTH) AF: 0.00 AC: 0 AN: 42242

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000284 AC: 4 AN: 140924 Hom.: 0 Cov.: 22 AF XY: 0.0000442 AC XY: 3 AN XY: 67876

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000105 AC: 4 AN: 38222

American (AMR) AF: 0.00 AC: 0 AN: 13626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3340

East Asian (EAS) AF: 0.00 AC: 0 AN: 4934

South Asian (SAS) AF: 0.00 AC: 0 AN: 4110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64652

Other (OTH) AF: 0.00 AC: 0 AN: 1804

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000135934), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jul 19, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.84
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1260372587; hg19: chr2-179518338;