rs2115558

Variant names:

• chr2-178612990-A-G
• rs2115558
• NM_001267550.2:c.49731T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178612990-A-G
• chr2-178612990-A-T

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.49731T>C​(p.His16577His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 1,612,542 control chromosomes in the GnomAD database, including 993 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (196 hom., cov: 32)
  • Exomes 𝑓: 0.021 (797 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: -0.0900
• Publications: 10 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=-0.64).
• BP6: Variant 2-178612990-A-G is Benign according to our data. Variant chr2-178612990-A-G is described in ClinVar as Benign. ClinVar VariationId is 47035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.127 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.49731T>C	p.His16577His	synonymous	Exon 265 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.44808T>C	p.His14936His	synonymous	Exon 215 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.42027T>C	p.His14009His	synonymous	Exon 214 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.49731T>C	p.His16577His	synonymous	Exon 265 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.49575T>C	p.His16525His	synonymous	Exon 263 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.49455T>C	p.His16485His	synonymous	Exon 263 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0386 AC: 5854 AN: 151712 Hom.: 194 Cov.: 32

Gnomad AFR AF: 0.0742

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0285

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.0542

Gnomad FIN AF: 0.0423

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.0374

GnomAD2 exomes AF: 0.0341 AC: 8472 AN: 248104 AF XY: 0.0346

Gnomad AFR exome AF: 0.0737

Gnomad AMR exome AF: 0.0140

Gnomad ASJ exome AF: 0.0256

Gnomad EAS exome AF: 0.134

Gnomad FIN exome AF: 0.0407

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.0295

GnomAD4 exome AF: 0.0209 AC: 30568 AN: 1460712 Hom.: 797 Cov.: 33 AF XY: 0.0220 AC XY: 16001 AN XY: 726662

African (AFR) AF: 0.0735 AC: 2457 AN: 33418

American (AMR) AF: 0.0152 AC: 677 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 663 AN: 26108

East Asian (EAS) AF: 0.137 AC: 5412 AN: 39512

South Asian (SAS) AF: 0.0576 AC: 4970 AN: 86224

European-Finnish (FIN) AF: 0.0404 AC: 2157 AN: 53384

Middle Eastern (MID) AF: 0.0420 AC: 242 AN: 5758

European-Non Finnish (NFE) AF: 0.0110 AC: 12174 AN: 1111328

Other (OTH) AF: 0.0301 AC: 1816 AN: 60310

GnomAD4 genome AF: 0.0386 AC: 5868 AN: 151830 Hom.: 196 Cov.: 32 AF XY: 0.0408 AC XY: 3025 AN XY: 74190

African (AFR) AF: 0.0743 AC: 3078 AN: 41450

American (AMR) AF: 0.0284 AC: 433 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3464

East Asian (EAS) AF: 0.136 AC: 692 AN: 5098

South Asian (SAS) AF: 0.0538 AC: 259 AN: 4810

European-Finnish (FIN) AF: 0.0423 AC: 447 AN: 10570

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0114 AC: 772 AN: 67878

Other (OTH) AF: 0.0393 AC: 83 AN: 2110

Alfa AF: 0.0226 Hom.: 65

Bravo AF: 0.0385

Asia WGS AF: 0.0890 AC: 309 AN: 3478

EpiCase AF: 0.0126

EpiControl AF: 0.0155

ClinVar

ClinVar submissions

Significance: 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	not provided (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.099
DANN	Benign	0.73
PhyloP100		-0.090
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2115558; hg19: chr2-179477717; COSMIC: COSV59946245; COSMIC: COSV59946245;