rs140319117

Variant names:

• chr2-178534344-G-A
• rs140319117
• NM_001267550.2:c.102271C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001267550.2(TTN):​c.102271C>T​(p.Arg34091Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00138 in 1,612,356 control chromosomes in the GnomAD database, including 2 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. R34091Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:19 O:1
• Conservation: PhyloP100: 5.72
• Publications: 22 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=0.012809247).
• BP6: Variant 2-178534344-G-A is Benign according to our data. Variant chr2-178534344-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178157.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

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.102271C>T	p.Arg34091Trp	missense	Exon 358 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.97348C>T	p.Arg32450Trp	missense	Exon 308 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.94567C>T	p.Arg31523Trp	missense	Exon 307 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.102271C>T	p.Arg34091Trp	missense	Exon 358 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.102115C>T	p.Arg34039Trp	missense	Exon 356 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.101995C>T	p.Arg33999Trp	missense	Exon 356 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000980 AC: 149 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00105 AC: 260 AN: 247286 AF XY: 0.000961

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00309

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000490

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00142 AC: 2070 AN: 1460160 Hom.: 2 Cov.: 38 AF XY: 0.00140 AC XY: 1018 AN XY: 726456

African (AFR) AF: 0.000299 AC: 10 AN: 33466

American (AMR) AF: 0.00139 AC: 62 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00287 AC: 75 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86258

European-Finnish (FIN) AF: 0.0000385 AC: 2 AN: 51962

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.00164 AC: 1819 AN: 1111794

Other (OTH) AF: 0.00136 AC: 82 AN: 60360

GnomAD4 genome AF: 0.000979 AC: 149 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.000954 AC XY: 71 AN XY: 74400

African (AFR) AF: 0.000241 AC: 10 AN: 41534

American (AMR) AF: 0.00124 AC: 19 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00153 AC: 104 AN: 68012

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00125 Hom.: 0

Bravo AF: 0.00111

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00157 AC: 13

ExAC AF: 0.00101 AC: 122

EpiCase AF: 0.00131

EpiControl AF: 0.00148

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	7	not provided (8)
-	-	5	not specified (5)
-	1	1	Myopathy, myofibrillar, 9, with early respiratory failure (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	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Primary dilated cardiomyopathy;C0018801:Heart failure (1)
-	-	1	Tibial muscular dystrophy (2)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Benign	0.96
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.34	N
PhyloP100		5.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D
Polyphen		1.0	D
Vest4		0.41
MVP		0.38
MPC		0.44
ClinPred		0.077	T
GERP RS		4.8
Mutation Taster		=19/81	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: rs140319117; hg19: chr2-179399071;