chr2-178709854-G-A

Variant names:

• chr2-178709854-G-A
• rs200489972
• NM_001267550.2:c.28465C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001267550.2(TTN):​c.28465C>T​(p.Arg9489Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000597 in 1,607,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. R9489Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: TTN NM_001267550.2 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: 5.86
• Publications: 1 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32937592).

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.28465C>T	p.Arg9489Trp	missense splice_region	Exon 99 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.27514C>T	p.Arg9172Trp	missense splice_region	Exon 97 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.24733C>T	p.Arg8245Trp	missense splice_region	Exon 96 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.28465C>T	p.Arg9489Trp	missense splice_region	Exon 99 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.28465C>T	p.Arg9489Trp	missense splice_region	Exon 99 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.28189C>T	p.Arg9397Trp	missense splice_region	Exon 97 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151982 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000486 AC: 12 AN: 246722 AF XY: 0.0000597

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000559

Gnomad FIN exome AF: 0.0000480

Gnomad NFE exome AF: 0.0000534

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.0000618 AC: 90 AN: 1455324 Hom.: 0 Cov.: 31 AF XY: 0.0000705 AC XY: 51 AN XY: 723210

African (AFR) AF: 0.0000301 AC: 1 AN: 33196

American (AMR) AF: 0.00 AC: 0 AN: 44380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39606

South Asian (SAS) AF: 0.000221 AC: 19 AN: 85782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.0000614 AC: 68 AN: 1108208

Other (OTH) AF: 0.0000166 AC: 1 AN: 60112

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151982 Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4 AN XY: 74242

African (AFR) AF: 0.0000484 AC: 2 AN: 41334

American (AMR) AF: 0.00 AC: 0 AN: 15262

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68008

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

Alfa AF: 0.0000566 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000331 AC: 4

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Benign	0.97
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.31	T
PhyloP100		5.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.28
MutPred		0.53		Loss of disorder (P = 0.0171)
MVP		0.38
MPC		0.47
ClinPred		0.55	D
GERP RS		5.0
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200489972; hg19: chr2-179574581;