rs188063446

Variant names:

• chr2-178592797-T-C
• rs188063446
• NM_001267550.2:c.59322A>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.59322A>G​(p.Pro19774Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000848 in 1,613,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P19774P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (0 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:18
• Conservation: PhyloP100: -0.0250
• Publications: 0 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=-0.54).
• BP6: Variant 2-178592797-T-C is Benign according to our data. Variant chr2-178592797-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47151.
• BP7: Synonymous conserved (PhyloP=-0.025 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.59322A>G	p.Pro19774Pro	synonymous	Exon 300 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.54399A>G	p.Pro18133Pro	synonymous	Exon 250 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.51618A>G	p.Pro17206Pro	synonymous	Exon 249 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.59322A>G	p.Pro19774Pro	synonymous	Exon 300 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.59166A>G	p.Pro19722Pro	synonymous	Exon 298 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.59046A>G	p.Pro19682Pro	synonymous	Exon 298 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 88 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000930 AC: 231 AN: 248340 AF XY: 0.000913

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000464

Gnomad NFE exome AF: 0.00183

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000877 AC: 1281 AN: 1461254 Hom.: 0 Cov.: 35 AF XY: 0.000857 AC XY: 623 AN XY: 726910

African (AFR) AF: 0.000209 AC: 7 AN: 33450

American (AMR) AF: 0.000246 AC: 11 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86236

European-Finnish (FIN) AF: 0.000768 AC: 41 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00105 AC: 1168 AN: 1111632

Other (OTH) AF: 0.000812 AC: 49 AN: 60354

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.000605 AC XY: 45 AN XY: 74428

African (AFR) AF: 0.000120 AC: 5 AN: 41590

American (AMR) AF: 0.000262 AC: 4 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00104 AC: 71 AN: 67986

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000743 Hom.: 0

Bravo AF: 0.000514

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.000600

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	6	not provided (6)
-	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	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	-0.54
CADD	Benign	0.91
DANN	Benign	0.64
PhyloP100		-0.025
Mutation Taster		=88/12	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: rs188063446; hg19: chr2-179457524;