rs202234492

Variant names:

• chr2-178733307-C-T
• rs202234492
• NM_001267550.2:c.15986G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_001267550.2(TTN):​c.15986G>A​(p.Gly5329Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000377 in 1,613,474 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).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:5
• Conservation: PhyloP100: 5.19
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2689629).
• BP6: Variant 2-178733307-C-T is Benign according to our data. Variant chr2-178733307-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203249.
• 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.15986G>A	p.Gly5329Asp	missense	Exon 54 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.15035G>A	p.Gly5012Asp	missense	Exon 52 of 313	NP_001243779.1
	TTN	NM_133378.4		c.12254G>A	p.Gly4085Asp	missense	Exon 51 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.15986G>A	p.Gly5329Asp	missense	Exon 54 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.15986G>A	p.Gly5329Asp	missense	Exon 54 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.15710G>A	p.Gly5237Asp	missense	Exon 52 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000407 AC: 101 AN: 247988 AF XY: 0.000446

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000732

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000385 AC: 563 AN: 1461284 Hom.: 2 Cov.: 36 AF XY: 0.000410 AC XY: 298 AN XY: 726918

African (AFR) AF: 0.000120 AC: 4 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86188

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000456 AC: 507 AN: 1111628

Other (OTH) AF: 0.000199 AC: 12 AN: 60362

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17 AN XY: 74340

African (AFR) AF: 0.0000482 AC: 2 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000495 Hom.: 1

Bravo AF: 0.000283

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000243 AC: 2

ExAC AF: 0.000455 AC: 55

EpiCase AF: 0.000655

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	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	Pathogenic	0.88
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Uncertain	0.050
CADD	Benign	22
DANN	Benign	0.88
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.27	T
MetaSVM	Pathogenic	0.81	D
PhyloP100		5.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.013	D
Polyphen		0.99	D
Vest4		0.38
MVP		0.61
MPC		0.46
ClinPred		0.12	T
GERP RS		5.9
Mutation Taster		=72/28	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: rs202234492; hg19: chr2-179598034; COSMIC: COSV60020470;