2-178698916-TAAAAAAAAAA-TAAAAAAAAA

Variant names:

• chr2-178698916-TA-T
• rs368277751
• NM_001267550.2:c.30683-3delT

Variant summary

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

The NM_001267550.2(TTN):​c.30683-3delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0042 (0 hom., cov: 30)
  • Exomes 𝑓: 0.28 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:8 O:1
• Conservation: PhyloP100: 0.401
• Publications: 3 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 2-178698916-TA-T is Benign according to our data. Variant chr2-178698916-TA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 332897.

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.30683-3delT		splice_region intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.29732-3delT		splice_region intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.26951-3delT		splice_region 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.30683-3delT		splice_region intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.30683-3delT		splice_region intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.30407-3delT		splice_region intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00414 AC: 352 AN: 85014 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00555

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00388

Gnomad SAS AF: 0.00206

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00428

Gnomad OTH AF: 0.00280

GnomAD2 exomes AF: 0.355 AC: 23344 AN: 65808 AF XY: 0.365

Gnomad AFR exome AF: 0.305

Gnomad AMR exome AF: 0.357

Gnomad ASJ exome AF: 0.400

Gnomad EAS exome AF: 0.354

Gnomad FIN exome AF: 0.350

Gnomad NFE exome AF: 0.338

Gnomad OTH exome AF: 0.363

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.282 AC: 278032 AN: 985106 Hom.: 0 Cov.: 0 AF XY: 0.285 AC XY: 138309 AN XY: 486012

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

African (AFR) AF: 0.319 AC: 6491 AN: 20378

American (AMR) AF: 0.309 AC: 5520 AN: 17860

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 5662 AN: 17288

East Asian (EAS) AF: 0.337 AC: 8637 AN: 25650

South Asian (SAS) AF: 0.307 AC: 15950 AN: 51922

European-Finnish (FIN) AF: 0.303 AC: 8273 AN: 27322

Middle Eastern (MID) AF: 0.277 AC: 922 AN: 3332

European-Non Finnish (NFE) AF: 0.275 AC: 214284 AN: 780098

Other (OTH) AF: 0.298 AC: 12293 AN: 41256

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00419 AC: 356 AN: 85034 Hom.: 0 Cov.: 30 AF XY: 0.00517 AC XY: 210 AN XY: 40594

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

African (AFR) AF: 0.00185 AC: 40 AN: 21588

American (AMR) AF: 0.00554 AC: 44 AN: 7936

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 17 AN: 2110

East Asian (EAS) AF: 0.00390 AC: 12 AN: 3080

South Asian (SAS) AF: 0.00207 AC: 6 AN: 2898

European-Finnish (FIN) AF: 0.0128 AC: 56 AN: 4370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 142

European-Non Finnish (NFE) AF: 0.00428 AC: 177 AN: 41310

Other (OTH) AF: 0.00371 AC: 4 AN: 1078

⚠️ 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.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	1	-	Dilated Cardiomyopathy, Dominant (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	1	-	Hypertrophic cardiomyopathy (1)
-	1	-	Limb-girdle muscular dystrophy, recessive (1)
-	1	-	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	1	-	Tibial muscular dystrophy (1)
-	-	-	Hypertrophic cardiomyopathy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.40
Mutation Taster		=97/3	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: rs368277751; hg19: chr2-179563643; COSMIC: COSV59904780; COSMIC: COSV59904780;