2-178602499-G-C

Variant names:

• chr2-178602499-G-C
• rs190830121
• NM_001267550.2:c.54903C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_001267550.2(TTN):​c.54903C>G​(p.Gly18301Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000667 in 1,610,838 control chromosomes in the GnomAD database, including 2 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 0.00076 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (1 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:17
• Conservation: PhyloP100: 0.0630
• 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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-178602499-G-C is Benign according to our data. Variant chr2-178602499-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 165971.
• BP7: Synonymous conserved (PhyloP=0.063 with no splicing effect.

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.54903C>G	p.Gly18301Gly	synonymous	Exon 283 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.49980C>G	p.Gly16660Gly	synonymous	Exon 233 of 313	NP_001243779.1
	TTN	NM_133378.4		c.47199C>G	p.Gly15733Gly	synonymous	Exon 232 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.54903C>G	p.Gly18301Gly	synonymous	Exon 283 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.54747C>G	p.Gly18249Gly	synonymous	Exon 281 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.54627C>G	p.Gly18209Gly	synonymous	Exon 281 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000764 AC: 116 AN: 151850 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.000591

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000567

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000898

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000736 AC: 180 AN: 244684 AF XY: 0.000791

Gnomad AFR exome AF: 0.000196

Gnomad AMR exome AF: 0.000852

Gnomad ASJ exome AF: 0.00181

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000328

Gnomad NFE exome AF: 0.000960

Gnomad OTH exome AF: 0.000505

GnomAD4 exome AF: 0.000657 AC: 958 AN: 1458872 Hom.: 1 Cov.: 32 AF XY: 0.000673 AC XY: 488 AN XY: 725558

African (AFR) AF: 0.000120 AC: 4 AN: 33372

American (AMR) AF: 0.000900 AC: 40 AN: 44444

Ashkenazi Jewish (ASJ) AF: 0.00249 AC: 65 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39346

South Asian (SAS) AF: 0.000395 AC: 34 AN: 85980

European-Finnish (FIN) AF: 0.000282 AC: 15 AN: 53244

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5750

European-Non Finnish (NFE) AF: 0.000679 AC: 754 AN: 1110438

Other (OTH) AF: 0.000747 AC: 45 AN: 60242

GnomAD4 genome AF: 0.000763 AC: 116 AN: 151966 Hom.: 1 Cov.: 32 AF XY: 0.000714 AC XY: 53 AN XY: 74272

African (AFR) AF: 0.000193 AC: 8 AN: 41510

American (AMR) AF: 0.000590 AC: 9 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.000567 AC: 6 AN: 10586

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

European-Non Finnish (NFE) AF: 0.000898 AC: 61 AN: 67912

Other (OTH) AF: 0.00143 AC: 3 AN: 2102

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000941

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	not provided (5)
-	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)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.3
DANN	Benign	0.67
PhyloP100		0.063
Mutation Taster		=90/10	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: rs190830121; hg19: chr2-179467226; COSMIC: COSV104640817;