rs115744476

Variant names:

• chr2-178682728-T-C
• rs115744476
• NM_001267550.2:c.33063A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001267550.2(TTN):​c.33063A>G​(p.Glu11021Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00861 in 1,612,750 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0062 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0089 (81 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:22
• Conservation: PhyloP100: -1.23
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-178682728-T-C is Benign according to our data. Variant chr2-178682728-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46884.
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00622 (945/152048) while in subpopulation AMR AF = 0.0152 (232/15248). AF 95% confidence interval is 0.0136. There are 3 homozygotes in GnomAd4. There are 461 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.33063A>G	p.Glu11021Glu	synonymous	Exon 135 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.32112A>G	p.Glu10704Glu	synonymous	Exon 133 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.29331A>G	p.Glu9777Glu	synonymous	Exon 132 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.33063A>G	p.Glu11021Glu	synonymous	Exon 135 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.33063A>G	p.Glu11021Glu	synonymous	Exon 135 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.32787A>G	p.Glu10929Glu	synonymous	Exon 133 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00622 AC: 945 AN: 151930 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0152

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00902

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00590 AC: 1466 AN: 248608 AF XY: 0.00576

Gnomad AFR exome AF: 0.00194

Gnomad AMR exome AF: 0.00903

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000744

Gnomad NFE exome AF: 0.00897

Gnomad OTH exome AF: 0.00680

GnomAD4 exome AF: 0.00886 AC: 12948 AN: 1460702 Hom.: 81 Cov.: 31 AF XY: 0.00866 AC XY: 6290 AN XY: 726606

African (AFR) AF: 0.00120 AC: 40 AN: 33446

American (AMR) AF: 0.00951 AC: 425 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00146 AC: 38 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00174 AC: 150 AN: 86080

European-Finnish (FIN) AF: 0.00107 AC: 57 AN: 53374

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5760

European-Non Finnish (NFE) AF: 0.0106 AC: 11762 AN: 1111280

Other (OTH) AF: 0.00756 AC: 456 AN: 60322

GnomAD4 genome AF: 0.00622 AC: 945 AN: 152048 Hom.: 3 Cov.: 32 AF XY: 0.00620 AC XY: 461 AN XY: 74328

African (AFR) AF: 0.00178 AC: 74 AN: 41562

American (AMR) AF: 0.0152 AC: 232 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.000470 AC: 5 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00902 AC: 612 AN: 67812

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00803 Hom.: 25

Bravo AF: 0.00652

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00818

EpiControl AF: 0.0115

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	7	not provided (7)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.26
DANN	Benign	0.38
PhyloP100		-1.2
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: rs115744476; hg19: chr2-179547455;