NM_001267550.2:c.100172-10dupT

Variant names:

• chr2-178536584-C-CA
• rs397517782
• NM_001267550.2:c.100172-10dupT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001267550.2(TTN):​c.100172-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0049 in 1,480,024 control chromosomes in the GnomAD database, including 45 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0046 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (41 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:15
• Conservation: PhyloP100: 1.72
• Publications: 1 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]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 2-178536584-C-CA is Benign according to our data. Variant chr2-178536584-C-CA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47626.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00457 (693/151632) while in subpopulation SAS AF = 0.00933 (45/4822). AF 95% confidence interval is 0.00717. There are 4 homozygotes in GnomAd4. There are 360 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

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.100172-10dupT		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.95249-10dupT		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.92468-10dupT		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.100172-10_100172-9insT		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.100016-10_100016-9insT		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.99896-10_99896-9insT		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00457 AC: 693 AN: 151514 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00538

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00932

Gnomad FIN AF: 0.00250

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00638

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00550 AC: 817 AN: 148510 AF XY: 0.00623

Gnomad AFR exome AF: 0.00116

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.00643

Gnomad OTH exome AF: 0.00680

GnomAD4 exome AF: 0.00494 AC: 6564 AN: 1328392 Hom.: 41 Cov.: 31 AF XY: 0.00524 AC XY: 3401 AN XY: 648882

African (AFR) AF: 0.000744 AC: 22 AN: 29556

American (AMR) AF: 0.00382 AC: 95 AN: 24842

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 318 AN: 19388

East Asian (EAS) AF: 0.0000530 AC: 2 AN: 37712

South Asian (SAS) AF: 0.0129 AC: 806 AN: 62400

European-Finnish (FIN) AF: 0.00268 AC: 110 AN: 41012

Middle Eastern (MID) AF: 0.0245 AC: 128 AN: 5230

European-Non Finnish (NFE) AF: 0.00453 AC: 4775 AN: 1053400

Other (OTH) AF: 0.00562 AC: 308 AN: 54852

GnomAD4 genome AF: 0.00457 AC: 693 AN: 151632 Hom.: 4 Cov.: 33 AF XY: 0.00486 AC XY: 360 AN XY: 74076

African (AFR) AF: 0.00102 AC: 42 AN: 41366

American (AMR) AF: 0.00538 AC: 82 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00933 AC: 45 AN: 4822

European-Finnish (FIN) AF: 0.00250 AC: 26 AN: 10394

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00638 AC: 433 AN: 67854

Other (OTH) AF: 0.00380 AC: 8 AN: 2104

Alfa AF: 0.00326 Hom.: 1

Bravo AF: 0.00412

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	not provided (4)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (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)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
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: rs397517782; hg19: chr2-179401311; COSMIC: COSV100635683; COSMIC: COSV100635683;