chr2-178642237-C-A

Variant names:

• chr2-178642237-C-A
• rs587780488
• NM_001267550.2:c.40558G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_001267550.2(TTN):​c.40558G>T​(p.Val13520Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000007 in 1,427,912 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V13520I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.19
• 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-178642237-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 515003.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.40558G>T	p.Val13520Phe	missense	Exon 219 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.35635G>T	p.Val11879Phe	missense	Exon 169 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.32854G>T	p.Val10952Phe	missense	Exon 168 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.40558G>T	p.Val13520Phe	missense	Exon 219 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000436599.2	TSL:1	c.40282G>T	p.Val13428Phe	missense	Exon 217 of 361	ENSP00000405517.2	A0A0C4DG59
	TTN	ENST00000446966.2	TSL:1	c.40478-1607G>T		intron	N/A	ENSP00000408004.2	A0A1B0GXE3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1427912 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 707112

⚠️ 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: 32812

American (AMR) AF: 0.00 AC: 0 AN: 40240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25474

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38452

South Asian (SAS) AF: 0.00 AC: 0 AN: 81024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1093488

Other (OTH) AF: 0.00 AC: 0 AN: 59050

⚠️ 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	Uncertain	0.48
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.038	T
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.24
Sift	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.21		Loss of MoRF binding (P = 0.098)
MVP		0.85
MPC		0.53
ClinPred		0.93	D
GERP RS		5.5
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.78		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587780488; hg19: chr2-179506964; COSMIC: COSV60247655; COSMIC: COSV60247655;