2-178587720-T-C

Variant names:

• chr2-178587720-T-C
• rs72646855
• NM_001267550.2:c.63589A>G

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.63589A>G​(p.Ile21197Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000742 in 1,612,896 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I21197T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (4 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:14
• Conservation: PhyloP100: 2.63
• Publications: 11 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=0.02718708).
• BP6: Variant 2-178587720-T-C is Benign according to our data. Variant chr2-178587720-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47197.
• BS2: High Homozygotes in GnomAdExome4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.63589A>G	p.Ile21197Val	missense	Exon 306 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.58666A>G	p.Ile19556Val	missense	Exon 256 of 313	NP_001243779.1
	TTN	NM_133378.4		c.55885A>G	p.Ile18629Val	missense	Exon 255 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.63589A>G	p.Ile21197Val	missense	Exon 306 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.63433A>G	p.Ile21145Val	missense	Exon 304 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.63313A>G	p.Ile21105Val	missense	Exon 304 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000546 AC: 83 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000971

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000581 AC: 144 AN: 247742 AF XY: 0.000610

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000373

Gnomad NFE exome AF: 0.000928

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000762 AC: 1113 AN: 1460726 Hom.: 4 Cov.: 33 AF XY: 0.000757 AC XY: 550 AN XY: 726642

African (AFR) AF: 0.000120 AC: 4 AN: 33422

American (AMR) AF: 0.000201 AC: 9 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39510

South Asian (SAS) AF: 0.000708 AC: 61 AN: 86194

European-Finnish (FIN) AF: 0.000431 AC: 23 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.000878 AC: 976 AN: 1111392

Other (OTH) AF: 0.000630 AC: 38 AN: 60322

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.000511 AC XY: 38 AN XY: 74404

African (AFR) AF: 0.000265 AC: 11 AN: 41560

American (AMR) AF: 0.000197 AC: 3 AN: 15266

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000971 AC: 66 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000844 Hom.: 1

Bravo AF: 0.000597

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000258 AC: 1

ESP6500EA AF: 0.000726 AC: 6

ExAC AF: 0.000637 AC: 77

EpiCase AF: 0.000546

EpiControl AF: 0.000653

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	4	not provided (8)
-	1	4	not specified (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	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Primary familial hypertrophic cardiomyopathy (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Benign	0.87
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.23	N
PhyloP100		2.6
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.082
Sift	Benign	0.47	T
Polyphen		0.0020	B
Vest4		0.33
MVP		0.42
MPC		0.071
ClinPred		0.0043	T
GERP RS		4.7
Mutation Taster		=95/5	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: rs72646855; hg19: chr2-179452447; COSMIC: COSV104641008;