2-178647040-GTATATATATA-GTATATA

Variant names:

• chr2-178647040-GTATA-G
• rs10580462
• NM_001267550.2:c.40222+20_40222+23delTATA

Variant summary

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

The NM_001267550.2(TTN):​c.40222+20_40222+23delTATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 714,078 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 0.00015 (0 hom., cov: 21)
  • Exomes 𝑓: 0.024 (0 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.346
• 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 2-178647040-GTATA-G is Benign according to our data. Variant chr2-178647040-GTATA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191975.

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.40222+20_40222+23delTATA		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.35375-1014_35375-1011delTATA		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.32594-1014_32594-1011delTATA		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.40222+20_40222+23delTATA		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.40222+20_40222+23delTATA		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.39946+20_39946+23delTATA		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000140 AC: 20 AN: 143182 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000758

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000280

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000448

Gnomad FIN AF: 0.000927

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000309

Gnomad OTH AF: 0.000514

GnomAD2 exomes AF: 0.0208 AC: 319 AN: 15314 AF XY: 0.0212

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.0805

Gnomad ASJ exome AF: 0.0323

Gnomad EAS exome AF: 0.00833

Gnomad FIN exome AF: 0.0128

Gnomad NFE exome AF: 0.0187

Gnomad OTH exome AF: 0.0392

GnomAD4 exome AF: 0.0244 AC: 13941 AN: 570836 Hom.: 0 AF XY: 0.0244 AC XY: 6916 AN XY: 283546

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

African (AFR) AF: 0.0813 AC: 993 AN: 12214

American (AMR) AF: 0.0606 AC: 424 AN: 6996

Ashkenazi Jewish (ASJ) AF: 0.0341 AC: 323 AN: 9470

East Asian (EAS) AF: 0.0286 AC: 532 AN: 18572

South Asian (SAS) AF: 0.0376 AC: 384 AN: 10220

European-Finnish (FIN) AF: 0.0250 AC: 682 AN: 27242

Middle Eastern (MID) AF: 0.0346 AC: 63 AN: 1822

European-Non Finnish (NFE) AF: 0.0212 AC: 9753 AN: 459848

Other (OTH) AF: 0.0322 AC: 787 AN: 24452

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000147 AC: 21 AN: 143242 Hom.: 0 Cov.: 21 AF XY: 0.000158 AC XY: 11 AN XY: 69488

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

African (AFR) AF: 0.0000756 AC: 3 AN: 39704

American (AMR) AF: 0.000280 AC: 4 AN: 14310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3370

East Asian (EAS) AF: 0.00 AC: 0 AN: 4868

South Asian (SAS) AF: 0.000450 AC: 2 AN: 4442

European-Finnish (FIN) AF: 0.000927 AC: 8 AN: 8632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.0000309 AC: 2 AN: 64810

Other (OTH) AF: 0.00102 AC: 2 AN: 1956

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 16

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs10580462; hg19: chr2-179511767;