NM_001267550.2:c.54189T>C

Variant names:

• chr2-178604988-A-G
• rs2303834
• NM_001267550.2:c.54189T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001267550.2(TTN):​c.54189T>C​(p.Tyr18063Tyr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000862 in 1,593,748 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (11 hom.)
• Consequence: TTN NM_001267550.2 splice_region, synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:20
• Conservation: PhyloP100: 0.868
• Publications: 6 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 2-178604988-A-G is Benign according to our data. Variant chr2-178604988-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47086.
• BP7: Synonymous conserved (PhyloP=0.868 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000743 (113/152076) while in subpopulation EAS AF = 0.0109 (56/5126). AF 95% confidence interval is 0.00864. There are 0 homozygotes in GnomAd4. There are 59 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.54189T>C	p.Tyr18063Tyr	splice_region synonymous	Exon 280 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.49266T>C	p.Tyr16422Tyr	splice_region synonymous	Exon 230 of 313	NP_001243779.1
	TTN	NM_133378.4		c.46485T>C	p.Tyr15495Tyr	splice_region synonymous	Exon 229 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.54189T>C	p.Tyr18063Tyr	splice_region synonymous	Exon 280 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.54033T>C	p.Tyr18011Tyr	splice_region synonymous	Exon 278 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.53913T>C	p.Tyr17971Tyr	splice_region synonymous	Exon 278 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000744 AC: 113 AN: 151958 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0109

Gnomad SAS AF: 0.00291

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000486

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00140 AC: 328 AN: 234324 AF XY: 0.00146

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000270

Gnomad ASJ exome AF: 0.000117

Gnomad EAS exome AF: 0.00999

Gnomad FIN exome AF: 0.000295

Gnomad NFE exome AF: 0.000712

Gnomad OTH exome AF: 0.000889

GnomAD4 exome AF: 0.000875 AC: 1261 AN: 1441672 Hom.: 11 Cov.: 32 AF XY: 0.000947 AC XY: 677 AN XY: 714750

African (AFR) AF: 0.00 AC: 0 AN: 32848

American (AMR) AF: 0.000208 AC: 9 AN: 43362

Ashkenazi Jewish (ASJ) AF: 0.000283 AC: 7 AN: 24772

East Asian (EAS) AF: 0.0124 AC: 490 AN: 39446

South Asian (SAS) AF: 0.00244 AC: 202 AN: 82860

European-Finnish (FIN) AF: 0.000228 AC: 12 AN: 52536

Middle Eastern (MID) AF: 0.000708 AC: 4 AN: 5648

European-Non Finnish (NFE) AF: 0.000431 AC: 474 AN: 1100746

Other (OTH) AF: 0.00106 AC: 63 AN: 59454

GnomAD4 genome AF: 0.000743 AC: 113 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.000794 AC XY: 59 AN XY: 74318

African (AFR) AF: 0.0000241 AC: 1 AN: 41540

American (AMR) AF: 0.000262 AC: 4 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0109 AC: 56 AN: 5126

South Asian (SAS) AF: 0.00291 AC: 14 AN: 4814

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000486 AC: 33 AN: 67934

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000839 Hom.: 2

Bravo AF: 0.000642

Asia WGS AF: 0.00953 AC: 33 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	-0.48
CADD	Benign	0.61
DANN	Benign	0.62
PhyloP100		0.87
Mutation Taster		=59/41	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: rs2303834; hg19: chr2-179469715; COSMIC: COSV59948274; COSMIC: COSV59948274;