rs766756026

Variant names:

• chr2-178682803-ATCATATTCTTCATATTCC-A
• rs766756026
• NM_001267550.2:c.32970_32987delGGAATATGAAGAATATGA

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM4 BP6

The NM_001267550.2(TTN):​c.32970_32987delGGAATATGAAGAATATGA​(p.Glu10990_Tyr10995del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,613,034 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: TTN NM_001267550.2 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 3.58
• 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 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001267550.2.
• BP6: Variant 2-178682803-ATCATATTCTTCATATTCC-A is Benign according to our data. Variant chr2-178682803-ATCATATTCTTCATATTCC-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194298.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.32970_32987delGGAATATGAAGAATATGA	p.Glu10990_Tyr10995del	disruptive_inframe_deletion	Exon 135 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.32019_32036delGGAATATGAAGAATATGA	p.Glu10673_Tyr10678del	disruptive_inframe_deletion	Exon 133 of 313	NP_001243779.1
	TTN	NM_133378.4		c.29238_29255delGGAATATGAAGAATATGA	p.Glu9746_Tyr9751del	disruptive_inframe_deletion	Exon 132 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.32970_32987delGGAATATGAAGAATATGA	p.Glu10990_Tyr10995del	disruptive_inframe_deletion	Exon 135 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.32970_32987delGGAATATGAAGAATATGA	p.Glu10990_Tyr10995del	disruptive_inframe_deletion	Exon 135 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.32694_32711delGGAATATGAAGAATATGA	p.Glu10898_Tyr10903del	disruptive_inframe_deletion	Exon 133 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 151910 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000884

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000362 AC: 90 AN: 248790 AF XY: 0.000318

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.00537

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000169 AC: 247 AN: 1461006 Hom.: 0 AF XY: 0.000175 AC XY: 127 AN XY: 726784

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.000403 AC: 18 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00429 AC: 112 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5760

European-Non Finnish (NFE) AF: 0.0000738 AC: 82 AN: 1111438

Other (OTH) AF: 0.000514 AC: 31 AN: 60330

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152028 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74300

African (AFR) AF: 0.0000722 AC: 3 AN: 41528

American (AMR) AF: 0.00131 AC: 20 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000884 AC: 6 AN: 67838

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000618 Hom.: 0

Bravo AF: 0.000321

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	1	-	Cardiomyopathy (1)
-	-	1	not specified (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6
Mutation Taster		=128/72	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs766756026; hg19: chr2-179547530;