rs778094750

Variant names:

• chr2-178608681-G-A
• rs778094750
• NM_001267550.2:c.52330C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178608681-G-A
• chr2-178608681-G-T

Variant summary

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

The NM_001267550.2(TTN):​c.52330C>T​(p.Arg17444Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000822 in 1,460,062 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. R17444H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.23
• Publications: 4 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 0 ACMG points.

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.52330C>T	p.Arg17444Cys	missense	Exon 274 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.47407C>T	p.Arg15803Cys	missense	Exon 224 of 313	NP_001243779.1
	TTN	NM_133378.4		c.44626C>T	p.Arg14876Cys	missense	Exon 223 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.52330C>T	p.Arg17444Cys	missense	Exon 274 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.52174C>T	p.Arg17392Cys	missense	Exon 272 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.52054C>T	p.Arg17352Cys	missense	Exon 272 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 246682 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1460062 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 726258

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39400

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111080

Other (OTH) AF: 0.0000166 AC: 1 AN: 60282

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000166 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Benign	0.84
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		6.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.73		Loss of MoRF binding (P = 0.0356)
MVP		0.75
MPC		0.51
ClinPred		0.64	D
GERP RS		4.8
Mutation Taster		=66/34	polymorphism

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: rs778094750; hg19: chr2-179473408; COSMIC: COSV59878854; COSMIC: COSV59878854;