2-178618267-G-A

Variant names:

• chr2-178618267-G-A
• rs72677231
• NM_001267550.2:c.47191C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.47191C>T​(p.Arg15731Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0034 in 1,612,720 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (10 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:22
• Conservation: PhyloP100: 5.17
• Publications: 16 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011384428).
• BP6: Variant 2-178618267-G-A is Benign according to our data. Variant chr2-178618267-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47007.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00224 (341/151996) while in subpopulation NFE AF = 0.00371 (252/67886). AF 95% confidence interval is 0.00334. There are 1 homozygotes in GnomAd4. There are 162 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.47191C>T	p.Arg15731Cys	missense	Exon 252 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.42268C>T	p.Arg14090Cys	missense	Exon 202 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.39487C>T	p.Arg13163Cys	missense	Exon 201 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.47191C>T	p.Arg15731Cys	missense	Exon 252 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.47035C>T	p.Arg15679Cys	missense	Exon 250 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.46915C>T	p.Arg15639Cys	missense	Exon 250 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 341 AN: 151878 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00204

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00371

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.00233 AC: 578 AN: 248102 AF XY: 0.00227

Gnomad AFR exome AF: 0.000712

Gnomad AMR exome AF: 0.00255

Gnomad ASJ exome AF: 0.00319

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000696

Gnomad NFE exome AF: 0.00360

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.00352 AC: 5142 AN: 1460724 Hom.: 10 Cov.: 32 AF XY: 0.00349 AC XY: 2535 AN XY: 726670

African (AFR) AF: 0.000509 AC: 17 AN: 33396

American (AMR) AF: 0.00231 AC: 103 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00326 AC: 85 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.000499 AC: 43 AN: 86228

European-Finnish (FIN) AF: 0.000656 AC: 35 AN: 53390

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5754

European-Non Finnish (NFE) AF: 0.00422 AC: 4684 AN: 1111262

Other (OTH) AF: 0.00275 AC: 166 AN: 60302

GnomAD4 genome AF: 0.00224 AC: 341 AN: 151996 Hom.: 1 Cov.: 33 AF XY: 0.00218 AC XY: 162 AN XY: 74312

African (AFR) AF: 0.000963 AC: 40 AN: 41530

American (AMR) AF: 0.00203 AC: 31 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00371 AC: 252 AN: 67886

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.00358 Hom.: 2

Bravo AF: 0.00235

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000517 AC: 2

ESP6500EA AF: 0.00289 AC: 24

ExAC AF: 0.00224 AC: 271

EpiCase AF: 0.00480

EpiControl AF: 0.00403

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	5	not provided (5)
-	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	Limb-girdle muscular dystrophy (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	0.83
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Benign	0.77
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		5.2
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.58
MVP		0.68
MPC		0.54
ClinPred		0.12	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=77/23	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: rs72677231; hg19: chr2-179482994;