chr2-178602584-G-C

Variant names:

• chr2-178602584-G-C
• rs201035511
• NM_001267550.2:c.54818C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001267550.2(TTN):​c.54818C>G​(p.Pro18273Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000074 in 1,351,246 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P18273L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.94
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.54818C>G	p.Pro18273Arg	missense	Exon 283 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.49895C>G	p.Pro16632Arg	missense	Exon 233 of 313	NP_001243779.1
	TTN	NM_133378.4		c.47114C>G	p.Pro15705Arg	missense	Exon 232 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.54818C>G	p.Pro18273Arg	missense	Exon 283 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.54662C>G	p.Pro18221Arg	missense	Exon 281 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.54542C>G	p.Pro18181Arg	missense	Exon 281 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.40e-7 AC: 1 AN: 1351246 Hom.: 0 Cov.: 32 AF XY: 0.00000151 AC XY: 1 AN XY: 663334

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29252

American (AMR) AF: 0.00 AC: 0 AN: 22782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22026

East Asian (EAS) AF: 0.00 AC: 0 AN: 36202

South Asian (SAS) AF: 0.00 AC: 0 AN: 70138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48724

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5368

European-Non Finnish (NFE) AF: 9.42e-7 AC: 1 AN: 1061022

Other (OTH) AF: 0.00 AC: 0 AN: 55732

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Benign	0.88
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		9.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D
Polyphen		0.16	B
Vest4		0.38
MutPred		0.51		Loss of glycosylation at P16632 (P = 0.0281)
MVP		0.67
MPC		0.10
ClinPred		0.69	D
GERP RS		4.9
Mutation Taster		=30/70	disease causing

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: rs201035511; hg19: chr2-179467311;