2-178591004-C-G

Variant names:

• chr2-178591004-C-G
• rs200212521
• NM_001267550.2:c.60721G>C

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.60721G>C​(p.Glu20241Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,613,484 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict 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. E20241E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:18
• Conservation: PhyloP100: 7.86
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016869813).
• BP6: Variant 2-178591004-C-G is Benign according to our data. Variant chr2-178591004-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47163.
• 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.60721G>C	p.Glu20241Gln	missense	Exon 304 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.55798G>C	p.Glu18600Gln	missense	Exon 254 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.53017G>C	p.Glu17673Gln	missense	Exon 253 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.60721G>C	p.Glu20241Gln	missense	Exon 304 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.60565G>C	p.Glu20189Gln	missense	Exon 302 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.60445G>C	p.Glu20149Gln	missense	Exon 302 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 171 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00121 AC: 300 AN: 247686 AF XY: 0.00109

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00432

Gnomad NFE exome AF: 0.00170

Gnomad OTH exome AF: 0.000831

GnomAD4 exome AF: 0.00133 AC: 1942 AN: 1461272 Hom.: 2 Cov.: 35 AF XY: 0.00132 AC XY: 960 AN XY: 726936

African (AFR) AF: 0.000179 AC: 6 AN: 33444

American (AMR) AF: 0.000224 AC: 10 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86244

European-Finnish (FIN) AF: 0.00371 AC: 198 AN: 53374

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5760

European-Non Finnish (NFE) AF: 0.00146 AC: 1626 AN: 1111576

Other (OTH) AF: 0.00116 AC: 70 AN: 60354

GnomAD4 genome AF: 0.00112 AC: 171 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74412

African (AFR) AF: 0.000217 AC: 9 AN: 41562

American (AMR) AF: 0.00210 AC: 32 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

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

European-Finnish (FIN) AF: 0.00386 AC: 41 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00126 AC: 86 AN: 67990

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00123 Hom.: 0

Bravo AF: 0.000831

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00133 AC: 11

ExAC AF: 0.00113 AC: 137

EpiCase AF: 0.00104

EpiControl AF: 0.00160

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	1	6	not specified (7)
-	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	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
1	-	-	Tip-toe gait (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Benign	0.91
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.37
MVP		0.34
MPC		0.46
ClinPred		0.075	T
GERP RS		6.1
Mutation Taster		=62/38	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: rs200212521; hg19: chr2-179455731;