rs201991864

Variant names:

• chr2-178682838-G-A
• rs201991864
• NM_001267550.2:c.32953C>T

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.32953C>T​(p.Arg10985Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,612,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 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. R10985P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:5
• Conservation: PhyloP100: 0.0350
• Publications: 3 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010427117).
• BP6: Variant 2-178682838-G-A is Benign according to our data. Variant chr2-178682838-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178226.

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.32953C>T	p.Arg10985Trp	missense	Exon 135 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.32002C>T	p.Arg10668Trp	missense	Exon 133 of 313	NP_001243779.1
	TTN	NM_133378.4		c.29221C>T	p.Arg9741Trp	missense	Exon 132 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.32953C>T	p.Arg10985Trp	missense	Exon 135 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.32953C>T	p.Arg10985Trp	missense	Exon 135 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.32677C>T	p.Arg10893Trp	missense	Exon 133 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 151634 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00462

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000278 AC: 69 AN: 248278 AF XY: 0.000282

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.000407

Gnomad ASJ exome AF: 0.00378

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000979

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000142 AC: 208 AN: 1460570 Hom.: 0 Cov.: 31 AF XY: 0.000147 AC XY: 107 AN XY: 726538

African (AFR) AF: 0.0000897 AC: 3 AN: 33434

American (AMR) AF: 0.000336 AC: 15 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00402 AC: 105 AN: 26100

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39626

South Asian (SAS) AF: 0.0000465 AC: 4 AN: 86074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53322

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5750

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1111294

Other (OTH) AF: 0.000547 AC: 33 AN: 60326

GnomAD4 genome AF: 0.000171 AC: 26 AN: 151634 Hom.: 0 Cov.: 32 AF XY: 0.000189 AC XY: 14 AN XY: 74046

African (AFR) AF: 0.00 AC: 0 AN: 41296

American (AMR) AF: 0.000131 AC: 2 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00462 AC: 16 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67800

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.000315 Hom.: 0

Bravo AF: 0.000212

ExAC AF: 0.000257 AC: 31

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	2	-	not specified (2)
-	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	-	Cardiomyopathy (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	0.14
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.75	T
PhyloP100		0.035
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.20
Sift	Uncertain	0.0040	D
Polyphen		0.0	B
Vest4		0.31
MVP		0.26
MPC		0.087
ClinPred		0.047	T
GERP RS		2.4
Mutation Taster		=92/8	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: rs201991864; hg19: chr2-179547565; COSMIC: COSV59914330;