rs200155485

Variant names:

• chr2-178583057-G-A
• rs200155485
• NM_001267550.2:c.65746C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178583057-G-A
• chr2-178583057-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001267550.2(TTN):​c.65746C>T​(p.Arg21916Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000683 in 1,610,924 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. R21916Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000065 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:3
• Conservation: PhyloP100: 2.63
• Publications: 6 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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11211395).
• BP6: Variant 2-178583057-G-A is Benign according to our data. Variant chr2-178583057-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 165891.

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.65746C>T	p.Arg21916Trp	missense	Exon 313 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.60823C>T	p.Arg20275Trp	missense	Exon 263 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.58042C>T	p.Arg19348Trp	missense	Exon 262 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.65746C>T	p.Arg21916Trp	missense	Exon 313 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.65590C>T	p.Arg21864Trp	missense	Exon 311 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.65470C>T	p.Arg21824Trp	missense	Exon 311 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0000987 AC: 15 AN: 151980 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00144

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: 0.000114 AC: 28 AN: 244946 AF XY: 0.0000753

Gnomad AFR exome AF: 0.0000657

Gnomad AMR exome AF: 0.0000587

Gnomad ASJ exome AF: 0.00180

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000452

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000651 AC: 95 AN: 1458944 Hom.: 1 Cov.: 30 AF XY: 0.0000537 AC XY: 39 AN XY: 725628

African (AFR) AF: 0.0000599 AC: 2 AN: 33384

American (AMR) AF: 0.0000449 AC: 2 AN: 44504

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 45 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39368

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 85944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53278

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5752

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1110402

Other (OTH) AF: 0.000116 AC: 7 AN: 60232

GnomAD4 genome AF: 0.0000987 AC: 15 AN: 151980 Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10 AN XY: 74212

African (AFR) AF: 0.0000725 AC: 3 AN: 41400

American (AMR) AF: 0.000197 AC: 3 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67962

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000296 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000240 AC: 2

ExAC AF: 0.000108 AC: 13

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Benign	0.89
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.46
MVP		0.34
MPC		0.45
ClinPred		0.20	T
GERP RS		2.9
Mutation Taster		=93/7	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: rs200155485; hg19: chr2-179447784; COSMIC: COSV60009809; COSMIC: COSV60009809;