2-178587294-C-T

Variant names:

• chr2-178587294-C-T
• rs202240487
• NM_001267550.2:c.63917G>A

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.63917G>A​(p.Arg21306His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000965 in 1,613,048 control chromosomes in the GnomAD database, including 19 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 0.00049 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (18 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:14
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073476136).
• BP6: Variant 2-178587294-C-T is Benign according to our data. Variant chr2-178587294-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47201.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000493 (75/152114) while in subpopulation SAS AF = 0.0131 (63/4816). AF 95% confidence interval is 0.0105. There are 1 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 18 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.63917G>A	p.Arg21306His	missense	Exon 307 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.58994G>A	p.Arg19665His	missense	Exon 257 of 313	NP_001243779.1
	TTN	NM_133378.4		c.56213G>A	p.Arg18738His	missense	Exon 256 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.63917G>A	p.Arg21306His	missense	Exon 307 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.63761G>A	p.Arg21254His	missense	Exon 305 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.63641G>A	p.Arg21214His	missense	Exon 305 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000500 AC: 76 AN: 151996 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00172 AC: 425 AN: 247608 AF XY: 0.00244

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.00101 AC: 1481 AN: 1460934 Hom.: 18 Cov.: 33 AF XY: 0.00138 AC XY: 1004 AN XY: 726766

African (AFR) AF: 0.0000897 AC: 3 AN: 33430

American (AMR) AF: 0.0000895 AC: 4 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39492

South Asian (SAS) AF: 0.0132 AC: 1135 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.000264 AC: 293 AN: 1111508

Other (OTH) AF: 0.000762 AC: 46 AN: 60328

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152114 Hom.: 1 Cov.: 32 AF XY: 0.000727 AC XY: 54 AN XY: 74328

African (AFR) AF: 0.0000482 AC: 2 AN: 41530

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

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.0131 AC: 63 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67962

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000169 Hom.: 0

Bravo AF: 0.000227

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.00196 AC: 237

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	1	2	not provided (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	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0073	T
MetaSVM	Uncertain	0.062	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.43
MVP		0.44
MPC		0.52
ClinPred		0.20	T
GERP RS		6.0
Mutation Taster		=98/2	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: rs202240487; hg19: chr2-179452021; COSMIC: COSV59981559; COSMIC: COSV59981559;