chr2-178645911-AT-A

Variant names:

• chr2-178645911-AT-A
• rs727504922
• NM_001267550.2:c.40408+8delA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS1

The NM_001267550.2(TTN):​c.40408+8delA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 1,531,222 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: TTN NM_001267550.2 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:7
• Conservation: PhyloP100: -0.0550
• Publications: 2 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 -5 ACMG points.

• BP6: Variant 2-178645911-AT-A is Benign according to our data. Variant chr2-178645911-AT-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 179522.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000244 (336/1379804) while in subpopulation MID AF = 0.0068 (38/5588). AF 95% confidence interval is 0.00509. There are 1 homozygotes in GnomAdExome4. There are 174 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check.

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.40408+8delA		splice_region intron	N/A	NP_001254479.2
	TTN	NM_001256850.1		c.35485+8delA		splice_region intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.32704+8delA		splice_region intron	N/A	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.40408+8delA		splice_region intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.40408+8delA		splice_region intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.40132+8delA		splice_region intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000297 AC: 45 AN: 151418 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000462

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.000482

GnomAD2 exomes AF: 0.000406 AC: 68 AN: 167650 AF XY: 0.000433

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000538

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.0000921

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000218

Gnomad OTH exome AF: 0.000741

GnomAD4 exome AF: 0.000244 AC: 336 AN: 1379804 Hom.: 1 Cov.: 28 AF XY: 0.000255 AC XY: 174 AN XY: 681902

African (AFR) AF: 0.0000329 AC: 1 AN: 30354

American (AMR) AF: 0.000450 AC: 15 AN: 33358

Ashkenazi Jewish (ASJ) AF: 0.00448 AC: 110 AN: 24536

East Asian (EAS) AF: 0.0000285 AC: 1 AN: 35054

South Asian (SAS) AF: 0.0000545 AC: 4 AN: 73460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50924

Middle Eastern (MID) AF: 0.00680 AC: 38 AN: 5588

European-Non Finnish (NFE) AF: 0.000121 AC: 129 AN: 1069406

Other (OTH) AF: 0.000665 AC: 38 AN: 57124

GnomAD4 genome AF: 0.000297 AC: 45 AN: 151418 Hom.: 0 Cov.: 31 AF XY: 0.000271 AC XY: 20 AN XY: 73840

African (AFR) AF: 0.00 AC: 0 AN: 41242

American (AMR) AF: 0.000462 AC: 7 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3468

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5130

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000280 AC: 19 AN: 67820

Other (OTH) AF: 0.000482 AC: 1 AN: 2074

Alfa AF: 0.000695 Hom.: 0

Bravo AF: 0.000382

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (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	-	Left ventricular noncompaction cardiomyopathy (1)
-	1	-	Limb-girdle muscular dystrophy, recessive (1)
-	1	-	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	not provided (1)
-	1	-	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.055
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: rs727504922; hg19: chr2-179510638;