2-178617838-C-T

Variant names:

• chr2-178617838-C-T
• rs199640194
• NM_001267550.2:c.47513G>A

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.47513G>A​(p.Arg15838Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000466 in 1,612,424 control chromosomes in the GnomAD database, including 1 homozygotes. 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).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:6
• Conservation: PhyloP100: 2.47
• Publications: 4 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05563882).
• BP6: Variant 2-178617838-C-T is Benign according to our data. Variant chr2-178617838-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195546.

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.47513G>A	p.Arg15838Gln	missense	Exon 253 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.42590G>A	p.Arg14197Gln	missense	Exon 203 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.39809G>A	p.Arg13270Gln	missense	Exon 202 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.47513G>A	p.Arg15838Gln	missense	Exon 253 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.47357G>A	p.Arg15786Gln	missense	Exon 251 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.47237G>A	p.Arg15746Gln	missense	Exon 251 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 151934 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000278 AC: 69 AN: 247874 AF XY: 0.000297

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000561

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.000500

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000489 AC: 714 AN: 1460490 Hom.: 1 Cov.: 32 AF XY: 0.000478 AC XY: 347 AN XY: 726566

African (AFR) AF: 0.000120 AC: 4 AN: 33386

American (AMR) AF: 0.000179 AC: 8 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86212

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53386

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5754

European-Non Finnish (NFE) AF: 0.000591 AC: 657 AN: 1111144

Other (OTH) AF: 0.000282 AC: 17 AN: 60280

GnomAD4 genome AF: 0.000250 AC: 38 AN: 151934 Hom.: 0 Cov.: 33 AF XY: 0.000256 AC XY: 19 AN XY: 74194

African (AFR) AF: 0.000266 AC: 11 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15236

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 67918

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000416 Hom.: 0

Bravo AF: 0.000238

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000512 AC: 2

ESP6500EA AF: 0.000601 AC: 5

ExAC AF: 0.000339 AC: 41

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000437

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	3	not provided (6)
-	2	1	not specified (3)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Benign	0.97
Eigen	Benign	-0.031
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.010	N
PhyloP100		2.5
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.082
Sift	Benign	0.32	T
Polyphen		0.054	B
Vest4		0.20
MVP		0.13
MPC		0.099
ClinPred		0.023	T
GERP RS		5.6
Mutation Taster		=96/4	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: rs199640194; hg19: chr2-179482565; COSMIC: COSV59953778; COSMIC: COSV59953778;