NM_001267550.2:c.53055G>A

Variant names:

• chr2-178607633-C-T
• rs200387466
• NM_001267550.2:c.53055G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001267550.2(TTN):​c.53055G>A​(p.Met17685Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,613,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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. M17685V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 3.53
• Publications: 7 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01152119).
• BP6: Variant 2-178607633-C-T is Benign according to our data. Variant chr2-178607633-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 165991.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000671 (102/152110) while in subpopulation AFR AF = 0.00238 (99/41546). AF 95% confidence interval is 0.002. There are 0 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.53055G>A	p.Met17685Ile	missense	Exon 277 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.48132G>A	p.Met16044Ile	missense	Exon 227 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.45351G>A	p.Met15117Ile	missense	Exon 226 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.53055G>A	p.Met17685Ile	missense	Exon 277 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.52899G>A	p.Met17633Ile	missense	Exon 275 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.52779G>A	p.Met17593Ile	missense	Exon 275 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000671 AC: 102 AN: 151992 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000145 AC: 36 AN: 247584 AF XY: 0.000119

Gnomad AFR exome AF: 0.00220

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000712 AC: 104 AN: 1460956 Hom.: 0 Cov.: 32 AF XY: 0.0000633 AC XY: 46 AN XY: 726780

African (AFR) AF: 0.00263 AC: 88 AN: 33430

American (AMR) AF: 0.0000447 AC: 2 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111444

Other (OTH) AF: 0.000166 AC: 10 AN: 60324

GnomAD4 genome AF: 0.000671 AC: 102 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.000605 AC XY: 45 AN XY: 74348

African (AFR) AF: 0.00238 AC: 99 AN: 41546

American (AMR) AF: 0.000196 AC: 3 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67940

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000313 Hom.: 0

Bravo AF: 0.000756

ESP6500AA AF: 0.00215 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000182 AC: 22

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	1	not specified (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.91
Eigen	Benign	0.0038
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.20	N
PhyloP100		3.5
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.18
Sift	Benign	0.11	T
Polyphen		0.017	B
Vest4		0.31
MutPred		0.49		Loss of MoRF binding (P = 0.0978)
MVP		0.49
MPC		0.098
ClinPred		0.043	T
GERP RS		6.2
Mutation Taster		=4/96	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: rs200387466; hg19: chr2-179472360;