rs2366751

Variant names:

• chr2-178562459-A-G
• rs2366751
• NM_001267550.2:c.83673T>C
• TTN p.Gly27891Gly

Your query was ambiguous. Multiple possible variants found:

• chr2-178562459-A-G
• chr2-178562459-A-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001267550.2(TTN):​c.83673T>C​(p.Gly27891Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,612,194 control chromosomes in the GnomAD database, including 74,727 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11870 hom., cov: 32)
  • Exomes 𝑓: 0.27 (62857 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 0.270
• Publications: 25 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 2-178562459-A-G is Benign according to our data. Variant chr2-178562459-A-G is described in ClinVar as Benign. ClinVar VariationId is 47429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.682 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.83673T>C	p.Gly27891Gly	synonymous	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.78750T>C	p.Gly26250Gly	synonymous	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.75969T>C	p.Gly25323Gly	synonymous	Exon 275 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.83673T>C	p.Gly27891Gly	synonymous	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.83517T>C	p.Gly27839Gly	synonymous	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.83397T>C	p.Gly27799Gly	synonymous	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.362 AC: 54944 AN: 151838 Hom.: 11821 Cov.: 32

Gnomad AFR AF: 0.542

Gnomad AMI AF: 0.563

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.701

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.279

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.328

GnomAD2 exomes AF: 0.351 AC: 86910 AN: 247520 AF XY: 0.348

Gnomad AFR exome AF: 0.544

Gnomad AMR exome AF: 0.425

Gnomad ASJ exome AF: 0.279

Gnomad EAS exome AF: 0.704

Gnomad FIN exome AF: 0.277

Gnomad NFE exome AF: 0.225

Gnomad OTH exome AF: 0.306

GnomAD4 exome AF: 0.268 AC: 391841 AN: 1460240 Hom.: 62857 Cov.: 39 AF XY: 0.273 AC XY: 198543 AN XY: 726320

African (AFR) AF: 0.556 AC: 18567 AN: 33418

American (AMR) AF: 0.424 AC: 18875 AN: 44482

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 7275 AN: 26058

East Asian (EAS) AF: 0.695 AC: 27538 AN: 39602

South Asian (SAS) AF: 0.503 AC: 43250 AN: 85966

European-Finnish (FIN) AF: 0.277 AC: 14753 AN: 53314

Middle Eastern (MID) AF: 0.306 AC: 1765 AN: 5760

European-Non Finnish (NFE) AF: 0.217 AC: 241564 AN: 1111338

Other (OTH) AF: 0.303 AC: 18254 AN: 60302

GnomAD4 genome AF: 0.362 AC: 55053 AN: 151954 Hom.: 11870 Cov.: 32 AF XY: 0.372 AC XY: 27646 AN XY: 74292

African (AFR) AF: 0.542 AC: 22471 AN: 41424

American (AMR) AF: 0.385 AC: 5870 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 987 AN: 3468

East Asian (EAS) AF: 0.701 AC: 3594 AN: 5128

South Asian (SAS) AF: 0.514 AC: 2479 AN: 4822

European-Finnish (FIN) AF: 0.285 AC: 3016 AN: 10564

Middle Eastern (MID) AF: 0.290 AC: 84 AN: 290

European-Non Finnish (NFE) AF: 0.226 AC: 15330 AN: 67970

Other (OTH) AF: 0.336 AC: 710 AN: 2112

Alfa AF: 0.282 Hom.: 10124

Bravo AF: 0.376

Asia WGS AF: 0.617 AC: 2146 AN: 3478

EpiCase AF: 0.220

EpiControl AF: 0.230

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	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	-0.43
CADD	Benign	0.26
DANN	Benign	0.66
PhyloP100		0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=81/19	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2366751;

hg19: chr2-179427186;

COSMIC: COSV60287420;

COSMIC: COSV60287420;