rs750715335

Variant names:

• chr2-178608216-C-T
• rs750715335
• NM_001267550.2:c.52667G>A

Variant summary

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

The NM_001267550.2(TTN):​c.52667G>A​(p.Ser17556Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,452,406 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S17556S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.86
• 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 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.52667G>A	p.Ser17556Asn	missense	Exon 275 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.47744G>A	p.Ser15915Asn	missense	Exon 225 of 313	NP_001243779.1
	TTN	NM_133378.4		c.44963G>A	p.Ser14988Asn	missense	Exon 224 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.52667G>A	p.Ser17556Asn	missense	Exon 275 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.52511G>A	p.Ser17504Asn	missense	Exon 273 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.52391G>A	p.Ser17464Asn	missense	Exon 273 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000125 AC: 3 AN: 240352 AF XY: 0.0000230

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: 0.0000183

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1452406 Hom.: 0 Cov.: 32 AF XY: 0.0000111 AC XY: 8 AN XY: 721336

African (AFR) AF: 0.00 AC: 0 AN: 33148

American (AMR) AF: 0.00 AC: 0 AN: 43864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25794

East Asian (EAS) AF: 0.00 AC: 0 AN: 39252

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1106878

Other (OTH) AF: 0.00 AC: 0 AN: 59904

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000470 Hom.: 0

ExAC AF: 0.00000829 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Aug 11, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser14988Asn variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/58268 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s750715335). Computational prediction tools and conservation analysis suggest th at the p.Ser14988Asn variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical signi ficance of the p.Ser14988Asn variant is unknown.

not provided Uncertain:1

Jul 22, 2024

Mayo Clinic Laboratories, Mayo Clinic

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	0.98
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Benign	0.89
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.56		Loss of glycosylation at S15915 (P = 0.0078)
MVP		0.49
MPC		0.45
ClinPred		0.40	T
GERP RS		5.7
Mutation Taster		=68/32	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: rs750715335; hg19: chr2-179472943;