chr2-178586727-G-A

Variant names:

• chr2-178586727-G-A
• rs72646859
• NM_001267550.2:c.64174C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The ENST00000589042.5(TTN):​c.64174C>T​(p.Arg21392Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0008 in 1,613,110 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. R21392H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (1 hom.)
• Consequence: TTN ENST00000589042.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:15
• Conservation: PhyloP100: 3.90
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05432737).
• BP6: Variant 2-178586727-G-A is Benign according to our data. Variant chr2-178586727-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47208.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000589042.5. 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.64174C>T	p.Arg21392Cys	missense	Exon 308 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.59251C>T	p.Arg19751Cys	missense	Exon 258 of 313	NP_001243779.1
	TTN	NM_133378.4		c.56470C>T	p.Arg18824Cys	missense	Exon 257 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.64174C>T	p.Arg21392Cys	missense	Exon 308 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.64018C>T	p.Arg21340Cys	missense	Exon 306 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.63898C>T	p.Arg21300Cys	missense	Exon 306 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152050 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000971

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000927

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000604 AC: 150 AN: 248548 AF XY: 0.000660

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00173

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000969

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000828 AC: 1210 AN: 1460942 Hom.: 1 Cov.: 33 AF XY: 0.000783 AC XY: 569 AN XY: 726764

African (AFR) AF: 0.0000898 AC: 3 AN: 33424

American (AMR) AF: 0.000201 AC: 9 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00124 AC: 49 AN: 39622

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5754

European-Non Finnish (NFE) AF: 0.000975 AC: 1084 AN: 1111380

Other (OTH) AF: 0.000945 AC: 57 AN: 60330

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74380

African (AFR) AF: 0.000144 AC: 6 AN: 41558

American (AMR) AF: 0.000458 AC: 7 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000973 AC: 5 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000927 AC: 63 AN: 67980

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

Alfa AF: 0.000824 Hom.: 0

Bravo AF: 0.000593

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00120 AC: 10

ExAC AF: 0.000662 AC: 80

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000928

EpiControl AF: 0.00113

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	6	not provided (9)
-	2	3	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	-	Hypertrophic cardiomyopathy (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	0.60
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	0.98
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.43
MVP		0.54
MPC		0.54
ClinPred		0.97	D
GERP RS		5.1
Mutation Taster		=81/19	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: rs72646859; hg19: chr2-179451454; COSMIC: COSV104644161; COSMIC: COSV104644161;