chr2-178702492-T-C

Variant names:

• chr2-178702492-T-C
• rs1057518758
• NM_001267550.2:c.30395A>G

Variant summary

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

The NM_001267550.2(TTN):​c.30395A>G​(p.His10132Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,696 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H10132D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02
• 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: 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.30395A>G	p.His10132Arg	missense	Exon 107 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.29444A>G	p.His9815Arg	missense	Exon 105 of 313	NP_001243779.1
	TTN	NM_133378.4		c.26663A>G	p.His8888Arg	missense	Exon 104 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.30395A>G	p.His10132Arg	missense	Exon 107 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.30395A>G	p.His10132Arg	missense	Exon 107 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.30119A>G	p.His10040Arg	missense	Exon 105 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461696 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727130

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111866

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bilateral talipes equinovarus;C1856694:Areflexia of lower limbs;C1858025:Spinal rigidity;C3277226:Restrictive ventilatory defect;C4015465:Thoracic kyphoscoliosis Uncertain:1

Jun 11, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.081	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.47	T
PhyloP100		8.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.40
Sift	Benign	0.35	T
Polyphen		0.97	D
Vest4		0.42
MutPred		0.79		Gain of phosphorylation at T9818 (P = 0.085)
MVP		0.33
MPC		0.40
ClinPred		0.45	T
GERP RS		4.6
PromoterAI		-0.052	Neutral
Mutation Taster		=39/61	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: rs1057518758; hg19: chr2-179567219;