NM_001267550.2:c.53780T>C

Variant names:

• chr2-178605515-A-G
• rs369678018
• NM_001267550.2:c.53780T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BP6

The NM_001267550.2(TTN):​c.53780T>C​(p.Leu17927Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,612,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 9.27
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826
• BP6: Variant 2-178605515-A-G is Benign according to our data. Variant chr2-178605515-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 202710.

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.53780T>C	p.Leu17927Pro	missense	Exon 279 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.48857T>C	p.Leu16286Pro	missense	Exon 229 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.46076T>C	p.Leu15359Pro	missense	Exon 228 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.53780T>C	p.Leu17927Pro	missense	Exon 279 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.53624T>C	p.Leu17875Pro	missense	Exon 277 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.53504T>C	p.Leu17835Pro	missense	Exon 277 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 151972 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000145 AC: 36 AN: 248156 AF XY: 0.000141

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.000258

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000168 AC: 246 AN: 1460344 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 127 AN XY: 726432

African (AFR) AF: 0.00 AC: 0 AN: 33390

American (AMR) AF: 0.0000448 AC: 2 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 86150

European-Finnish (FIN) AF: 0.000281 AC: 15 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.000200 AC: 222 AN: 1110986

Other (OTH) AF: 0.000116 AC: 7 AN: 60302

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 151972 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74196

African (AFR) AF: 0.0000241 AC: 1 AN: 41422

American (AMR) AF: 0.000131 AC: 2 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67936

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000245 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000243 AC: 2

ExAC AF: 0.000182 AC: 22

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	2	not specified (3)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	23
DANN	Benign	0.94
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		9.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D
Polyphen		1.0	D
Vest4		0.68
MVP		0.94
MPC		0.59
ClinPred		0.25	T
GERP RS		5.7
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs369678018; hg19: chr2-179470242;