2-178713381-TACAAAACAAAACAAA-TACAAA

Variant names:

• chr2-178713381-TACAAAACAAA-T
• rs71393436
• NM_001267550.2:c.26762-19_26762-10delTTTGTTTTGT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001267550.2(TTN):​c.26762-19_26762-10delTTTGTTTTGT variant causes a intron change. The variant allele was found at a frequency of 0.000203 in 1,469,042 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 24)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.61
• Publications: 4 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 2-178713381-TACAAAACAAA-T is Benign according to our data. Variant chr2-178713381-TACAAAACAAA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 413103.

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.26762-19_26762-10delTTTGTTTTGT		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.25811-19_25811-10delTTTGTTTTGT		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.23030-19_23030-10delTTTGTTTTGT		intron	N/A	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.26762-19_26762-10delTTTGTTTTGT		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.26762-19_26762-10delTTTGTTTTGT		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.26486-19_26486-10delTTTGTTTTGT		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000205 AC: 31 AN: 150896 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.000633

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.000482

GnomAD4 exome AF: 0.000203 AC: 267 AN: 1318030 Hom.: 0 AF XY: 0.000184 AC XY: 118 AN XY: 641896

African (AFR) AF: 0.000280 AC: 8 AN: 28588

American (AMR) AF: 0.000136 AC: 3 AN: 22038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21172

East Asian (EAS) AF: 0.0000874 AC: 3 AN: 34336

South Asian (SAS) AF: 0.000688 AC: 43 AN: 62460

European-Finnish (FIN) AF: 0.0000213 AC: 1 AN: 46854

Middle Eastern (MID) AF: 0.000499 AC: 2 AN: 4006

European-Non Finnish (NFE) AF: 0.000192 AC: 200 AN: 1044272

Other (OTH) AF: 0.000129 AC: 7 AN: 54304

GnomAD4 genome AF: 0.000205 AC: 31 AN: 151012 Hom.: 0 Cov.: 24 AF XY: 0.000163 AC XY: 12 AN XY: 73704

African (AFR) AF: 0.000146 AC: 6 AN: 41028

American (AMR) AF: 0.0000660 AC: 1 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000198 AC: 1 AN: 5054

South Asian (SAS) AF: 0.000634 AC: 3 AN: 4732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000280 AC: 19 AN: 67802

Other (OTH) AF: 0.000477 AC: 1 AN: 2098

Alfa AF: 0.0000893 Hom.: 211

Bravo AF: 0.000166

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs71393436; hg19: chr2-179578108;