rs12993099

Variant names:

• chr2-178733501-A-G
• rs12993099
• NM_001267550.2:c.15792T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001267550.2(TTN):​c.15792T>C​(p.Ile5264Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.067 in 1,610,452 control chromosomes in the GnomAD database, including 4,204 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (359 hom., cov: 33)
  • Exomes 𝑓: 0.068 (3845 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 2.08
• Publications: 11 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 2-178733501-A-G is Benign according to our data. Variant chr2-178733501-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0798 is higher than 0.05.

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.15792T>C	p.Ile5264Ile	synonymous	Exon 54 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.14841T>C	p.Ile4947Ile	synonymous	Exon 52 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.12060T>C	p.Ile4020Ile	synonymous	Exon 51 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.15792T>C	p.Ile5264Ile	synonymous	Exon 54 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.15792T>C	p.Ile5264Ile	synonymous	Exon 54 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.15516T>C	p.Ile5172Ile	synonymous	Exon 52 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0550 AC: 8363 AN: 152168 Hom.: 359 Cov.: 33

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.0667

Gnomad ASJ AF: 0.0689

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.0431

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0816

Gnomad OTH AF: 0.0747

GnomAD2 exomes AF: 0.0531 AC: 13114 AN: 246996 AF XY: 0.0540

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.0445

Gnomad ASJ exome AF: 0.0602

Gnomad EAS exome AF: 0.000223

Gnomad FIN exome AF: 0.0460

Gnomad NFE exome AF: 0.0796

Gnomad OTH exome AF: 0.0720

GnomAD4 exome AF: 0.0683 AC: 99559 AN: 1458166 Hom.: 3845 Cov.: 36 AF XY: 0.0671 AC XY: 48624 AN XY: 724808

African (AFR) AF: 0.0128 AC: 425 AN: 33312

American (AMR) AF: 0.0478 AC: 2129 AN: 44502

Ashkenazi Jewish (ASJ) AF: 0.0618 AC: 1609 AN: 26048

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39624

South Asian (SAS) AF: 0.0174 AC: 1500 AN: 86010

European-Finnish (FIN) AF: 0.0456 AC: 2430 AN: 53280

Middle Eastern (MID) AF: 0.137 AC: 786 AN: 5748

European-Non Finnish (NFE) AF: 0.0784 AC: 86932 AN: 1109460

Other (OTH) AF: 0.0621 AC: 3740 AN: 60182

GnomAD4 genome AF: 0.0549 AC: 8363 AN: 152286 Hom.: 359 Cov.: 33 AF XY: 0.0535 AC XY: 3986 AN XY: 74460

African (AFR) AF: 0.0129 AC: 536 AN: 41570

American (AMR) AF: 0.0666 AC: 1019 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0689 AC: 239 AN: 3470

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5182

South Asian (SAS) AF: 0.0149 AC: 72 AN: 4826

European-Finnish (FIN) AF: 0.0431 AC: 457 AN: 10614

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0816 AC: 5548 AN: 68012

Other (OTH) AF: 0.0744 AC: 157 AN: 2110

Alfa AF: 0.0630 Hom.: 306

Bravo AF: 0.0555

Asia WGS AF: 0.0100 AC: 36 AN: 3476

EpiCase AF: 0.0833

EpiControl AF: 0.0882

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	4.7
DANN	Benign	0.74
PhyloP100		2.1
Mutation Taster		=91/9	polymorphism (auto)

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: rs12993099; hg19: chr2-179598228;