rs201057307

Variant names:

• chr2-178621119-G-C
• rs201057307
• NM_001267550.2:c.45599C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001267550.2(TTN):​c.45599C>G​(p.Ala15200Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,612,210 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A15200T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:13
• Conservation: PhyloP100: 9.94
• Publications: 8 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009018153).
• BP6: Variant 2-178621119-G-C is Benign according to our data. Variant chr2-178621119-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46991.

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.45599C>G	p.Ala15200Gly	missense	Exon 246 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.40676C>G	p.Ala13559Gly	missense	Exon 196 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.37895C>G	p.Ala12632Gly	missense	Exon 195 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.45599C>G	p.Ala15200Gly	missense	Exon 246 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.45443C>G	p.Ala15148Gly	missense	Exon 244 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.45323C>G	p.Ala15108Gly	missense	Exon 244 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 46 AN: 151892 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00953

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000586 AC: 145 AN: 247242 AF XY: 0.000529

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000584

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000197

Gnomad OTH exome AF: 0.000834

GnomAD4 exome AF: 0.000346 AC: 505 AN: 1460318 Hom.: 1 Cov.: 32 AF XY: 0.000368 AC XY: 267 AN XY: 726442

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.0000673 AC: 3 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 339 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39470

South Asian (SAS) AF: 0.0000697 AC: 6 AN: 86108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5756

European-Non Finnish (NFE) AF: 0.0000801 AC: 89 AN: 1111276

Other (OTH) AF: 0.00101 AC: 61 AN: 60296

GnomAD4 genome AF: 0.000303 AC: 46 AN: 151892 Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21 AN XY: 74166

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.0000657 AC: 1 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00953 AC: 33 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67906

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.00170 Hom.: 0

Bravo AF: 0.000385

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000969 AC: 8

ExAC AF: 0.000422 AC: 51

EpiCase AF: 0.000437

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	1	3	not specified (4)
1	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	1	1	Dilated cardiomyopathy 1G (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	23
DANN	Benign	0.93
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.012	D
Polyphen		0.43	B
Vest4		0.39
MVP		0.33
MPC		0.11
ClinPred		0.16	T
GERP RS		5.7
Mutation Taster		=3/97	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: rs201057307; hg19: chr2-179485846;