rs200042932

Variant names:

• chr2-178620030-C-T
• rs200042932
• NM_001267550.2:c.46387G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178620030-C-T
• chr2-178620030-C-G

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.46387G>A​(p.Gly15463Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00044 in 1,611,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G15463G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:6
• Conservation: PhyloP100: 7.80
• Publications: 7 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=0.18501413).
• BP6: Variant 2-178620030-C-T is Benign according to our data. Variant chr2-178620030-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47000.

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.46387G>A	p.Gly15463Arg	missense	Exon 249 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.41464G>A	p.Gly13822Arg	missense	Exon 199 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.38683G>A	p.Gly12895Arg	missense	Exon 198 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.46387G>A	p.Gly15463Arg	missense	Exon 249 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.46231G>A	p.Gly15411Arg	missense	Exon 247 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.46111G>A	p.Gly15371Arg	missense	Exon 247 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000264 AC: 40 AN: 151754 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000339

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000292 AC: 72 AN: 246698 AF XY: 0.000269

Gnomad AFR exome AF: 0.000324

Gnomad AMR exome AF: 0.0000583

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.0000564

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.000512

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000457 AC: 667 AN: 1459898 Hom.: 0 Cov.: 31 AF XY: 0.000425 AC XY: 309 AN XY: 726212

African (AFR) AF: 0.000150 AC: 5 AN: 33370

American (AMR) AF: 0.000112 AC: 5 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 4 AN: 26056

East Asian (EAS) AF: 0.000329 AC: 13 AN: 39484

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86140

European-Finnish (FIN) AF: 0.000319 AC: 17 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.000551 AC: 612 AN: 1110894

Other (OTH) AF: 0.000116 AC: 7 AN: 60262

GnomAD4 genome AF: 0.000277 AC: 42 AN: 151872 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74234

African (AFR) AF: 0.000362 AC: 15 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5116

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000339 AC: 23 AN: 67856

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000362 Hom.: 0

Bravo AF: 0.000242

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000271 AC: 1

ESP6500EA AF: 0.000365 AC: 3

ExAC AF: 0.000339 AC: 41

Asia WGS AF: 0.000289 AC: 1 AN: 3476

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	1	not provided (4)
-	1	2	not specified (3)
-	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	Cardiovascular phenotype (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)
-	1	-	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Benign	0.96
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.72	N
PhyloP100		7.8
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.46
Sift	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.60
MutPred		0.48		Gain of disorder (P = 0.0444)
MVP		0.73
MPC		0.51
ClinPred		0.80	D
GERP RS		5.7
Mutation Taster		=45/55	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200042932; hg19: chr2-179484757;