chr2-178599244-A-G

Variant names:

• chr2-178599244-A-G
• rs878854317
• NM_001267550.2:c.56549T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001267550.2(TTN):​c.56549T>C​(p.Leu18850Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000713 in 1,403,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L18850Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.05
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774

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.56549T>C	p.Leu18850Pro	missense	Exon 290 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.51626T>C	p.Leu17209Pro	missense	Exon 240 of 313	NP_001243779.1
	TTN	NM_133378.4		c.48845T>C	p.Leu16282Pro	missense	Exon 239 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.56549T>C	p.Leu18850Pro	missense	Exon 290 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.56393T>C	p.Leu18798Pro	missense	Exon 288 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.56273T>C	p.Leu18758Pro	missense	Exon 288 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1403458 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 693478

African (AFR) AF: 0.00 AC: 0 AN: 31112

American (AMR) AF: 0.00 AC: 0 AN: 33920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22544

East Asian (EAS) AF: 0.00 AC: 0 AN: 38924

South Asian (SAS) AF: 0.0000136 AC: 1 AN: 73684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51634

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5502

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088226

Other (OTH) AF: 0.00 AC: 0 AN: 57912

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	0.0046	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Benign	0.93
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.9	M
PhyloP100		5.1
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.32
Sift	Benign	0.12	T
Polyphen		0.99	D
Vest4		0.70
MutPred		0.56		Loss of catalytic residue at L17209 (P = 0.0259)
MVP		0.66
MPC		0.49
ClinPred		0.35	T
GERP RS		5.9
Mutation Taster		=61/39	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: rs878854317; hg19: chr2-179463971;