rs762214300

Variant names:

• chr2-178608294-T-C
• rs762214300
• NM_001267550.2:c.52589A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001267550.2(TTN):​c.52589A>G​(p.Asn17530Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,612,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. N17530N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.40
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16567603).

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.52589A>G	p.Asn17530Ser	missense	Exon 275 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.47666A>G	p.Asn15889Ser	missense	Exon 225 of 313	NP_001243779.1
	TTN	NM_133378.4		c.44885A>G	p.Asn14962Ser	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.52589A>G	p.Asn17530Ser	missense	Exon 275 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.52433A>G	p.Asn17478Ser	missense	Exon 273 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.52313A>G	p.Asn17438Ser	missense	Exon 273 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151988 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000607 AC: 15 AN: 246936 AF XY: 0.0000299

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000933

Gnomad NFE exome AF: 0.0000985

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000452 AC: 66 AN: 1460160 Hom.: 0 Cov.: 32 AF XY: 0.0000372 AC XY: 27 AN XY: 726312

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

American (AMR) AF: 0.0000672 AC: 3 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39436

South Asian (SAS) AF: 0.00 AC: 0 AN: 86114

European-Finnish (FIN) AF: 0.000188 AC: 10 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000459 AC: 51 AN: 1111168

Other (OTH) AF: 0.0000332 AC: 2 AN: 60276

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151988 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74214

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67932

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000330 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.000124 AC: 15

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Benign	0.87
Eigen	Benign	-0.16
Eigen_PC	Benign	0.038
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.76	N
PhyloP100		1.4
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.096
Sift	Benign	0.039	D
Polyphen		0.027	B
Vest4		0.26
MutPred		0.43		Loss of stability (P = 0.0624)
MVP		0.17
MPC		0.077
ClinPred		0.040	T
GERP RS		5.7
Mutation Taster		=95/5	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: rs762214300; hg19: chr2-179473021;