NM_001267550.2:c.62330G>A

Variant names:

• chr2-178589395-C-T
• rs786205541
• NM_001267550.2:c.62330G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_001267550.2(TTN):​c.62330G>A​(p.Gly20777Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,268 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G20777G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.04
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-178589395-C-T is Pathogenic according to our data. Variant chr2-178589395-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 191137.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3683022). . Strength limited to SUPPORTING due to the PP5.

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.62330G>A	p.Gly20777Glu	missense	Exon 304 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.57407G>A	p.Gly19136Glu	missense	Exon 254 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.54626G>A	p.Gly18209Glu	missense	Exon 253 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.62330G>A	p.Gly20777Glu	missense	Exon 304 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.62174G>A	p.Gly20725Glu	missense	Exon 302 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.62054G>A	p.Gly20685Glu	missense	Exon 302 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461268 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726934

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111670

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Benign	0.83
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.53	N
PhyloP100		6.0
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.51
MutPred		0.52		Gain of ubiquitination at K19141 (P = 0.0598)
MVP		0.30
MPC		0.52
ClinPred		0.62	D
GERP RS		5.8
Mutation Taster		=52/48	disease causing (ClinVar)

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: rs786205541; hg19: chr2-179454122;