rs397517549

Variant names:

• chr2-178677662-ACTT-A
• rs397517549
• NM_001267550.2:c.34247_34249delAAG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_001267550.2(TTN):​c.34247_34249delAAG​(p.Glu11416del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,612,234 control chromosomes in the GnomAD database, including 49 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E11416E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00065 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (46 hom.)
• Consequence: TTN NM_001267550.2 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:9
• Conservation: PhyloP100: 3.53
• Publications: 5 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: Benign. The variant received -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001267550.2. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 2-178677662-ACTT-A is Benign according to our data. Variant chr2-178677662-ACTT-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46901.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000652 (99/151880) while in subpopulation SAS AF = 0.0175 (84/4812). AF 95% confidence interval is 0.0144. There are 3 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.34247_34249delAAG	p.Glu11416del	disruptive_inframe_deletion	Exon 146 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.33296_33298delAAG	p.Glu11099del	disruptive_inframe_deletion	Exon 144 of 313	NP_001243779.1
	TTN	NM_133378.4		c.30515_30517delAAG	p.Glu10172del	disruptive_inframe_deletion	Exon 143 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.34247_34249delAAG	p.Glu11416del	disruptive_inframe_deletion	Exon 146 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.34247_34249delAAG	p.Glu11416del	disruptive_inframe_deletion	Exon 146 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.33971_33973delAAG	p.Glu11324del	disruptive_inframe_deletion	Exon 144 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000659 AC: 100 AN: 151762 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00244 AC: 606 AN: 248298 AF XY: 0.00321

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000311

Gnomad OTH exome AF: 0.000666

GnomAD4 exome AF: 0.00116 AC: 1690 AN: 1460354 Hom.: 46 AF XY: 0.00159 AC XY: 1157 AN XY: 726434

African (AFR) AF: 0.0000898 AC: 3 AN: 33396

American (AMR) AF: 0.0000673 AC: 3 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39668

South Asian (SAS) AF: 0.0159 AC: 1372 AN: 86138

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53354

Middle Eastern (MID) AF: 0.000696 AC: 4 AN: 5748

European-Non Finnish (NFE) AF: 0.000198 AC: 220 AN: 1111138

Other (OTH) AF: 0.00139 AC: 84 AN: 60304

GnomAD4 genome AF: 0.000652 AC: 99 AN: 151880 Hom.: 3 Cov.: 32 AF XY: 0.00104 AC XY: 77 AN XY: 74244

African (AFR) AF: 0.0000482 AC: 2 AN: 41452

American (AMR) AF: 0.000197 AC: 3 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.0175 AC: 84 AN: 4812

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67872

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.000189

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	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	-	Primary familial hypertrophic cardiomyopathy (1)
-	1	-	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5
Mutation Taster		=77/23	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: rs397517549; hg19: chr2-179542389; COSMIC: COSV60431445;