NM_001267550.2:c.33513_33515dupAGA

Variant names:

• chr2-178679958-C-CTCT
• rs368327166
• NM_001267550.2:c.33513_33515dupAGA

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.33513_33515dupAGA​(p.Glu11172dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0162 in 1,613,012 control chromosomes in the GnomAD database, including 231 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (10 hom., cov: 32)
  • Exomes 𝑓: 0.017 (221 hom.)
• Consequence: TTN NM_001267550.2 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:17
• Conservation: PhyloP100: 3.88
• Publications: 6 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 2-178679958-C-CTCT is Benign according to our data. Variant chr2-178679958-C-CTCT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46889.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0111 (1687/152018) while in subpopulation NFE AF = 0.0185 (1258/67912). AF 95% confidence interval is 0.0177. There are 10 homozygotes in GnomAd4. There are 750 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.33513_33515dupAGA	p.Glu11172dup	disruptive_inframe_insertion	Exon 140 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.32562_32564dupAGA	p.Glu10855dup	disruptive_inframe_insertion	Exon 138 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.29781_29783dupAGA	p.Glu9928dup	disruptive_inframe_insertion	Exon 137 of 312	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.33513_33515dupAGA	p.Glu11172dup	disruptive_inframe_insertion	Exon 140 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.33513_33515dupAGA	p.Glu11172dup	disruptive_inframe_insertion	Exon 140 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.33237_33239dupAGA	p.Glu11080dup	disruptive_inframe_insertion	Exon 138 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1687 AN: 151900 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00321

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00513

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.00814

GnomAD2 exomes AF: 0.0113 AC: 2798 AN: 248470 AF XY: 0.0115

Gnomad AFR exome AF: 0.00356

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.00697

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.0179

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.0167 AC: 24446 AN: 1460994 Hom.: 221 Cov.: 32 AF XY: 0.0164 AC XY: 11903 AN XY: 726796

African (AFR) AF: 0.00272 AC: 91 AN: 33444

American (AMR) AF: 0.00452 AC: 202 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00590 AC: 154 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00597 AC: 515 AN: 86222

European-Finnish (FIN) AF: 0.0140 AC: 747 AN: 53394

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5760

European-Non Finnish (NFE) AF: 0.0198 AC: 21980 AN: 1111378

Other (OTH) AF: 0.0123 AC: 743 AN: 60352

GnomAD4 genome AF: 0.0111 AC: 1687 AN: 152018 Hom.: 10 Cov.: 32 AF XY: 0.0101 AC XY: 750 AN XY: 74328

African (AFR) AF: 0.00320 AC: 133 AN: 41500

American (AMR) AF: 0.00512 AC: 78 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4828

European-Finnish (FIN) AF: 0.0141 AC: 149 AN: 10594

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

European-Non Finnish (NFE) AF: 0.0185 AC: 1258 AN: 67912

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00623 Hom.: 0

Bravo AF: 0.0101

EpiCase AF: 0.0164

EpiControl AF: 0.0176

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	9	not specified (10)
-	-	4	not provided (4)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Primary dilated cardiomyopathy;C1142166:Brugada syndrome (1)
-	1	-	Ventricular fibrillation, paroxysmal familial, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.9
Mutation Taster		=76/24	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs368327166; hg19: chr2-179544685; COSMIC: COSV59905524;