NM_001267550.2:c.25937G>A

Variant names:

• chr2-178715249-C-T
• rs144587343
• NM_001267550.2:c.25937G>A

Variant summary

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

The NM_001267550.2(TTN):​c.25937G>A​(p.Arg8646His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,601,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 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. R8646C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: -0.321
• Publications: 4 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=0.02284503).
• BP6: Variant 2-178715249-C-T is Benign according to our data. Variant chr2-178715249-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 263481.

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.25937G>A	p.Arg8646His	missense	Exon 90 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.24986G>A	p.Arg8329His	missense	Exon 88 of 313	NP_001243779.1
	TTN	NM_133378.4		c.22205G>A	p.Arg7402His	missense	Exon 87 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.25937G>A	p.Arg8646His	missense	Exon 90 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.25937G>A	p.Arg8646His	missense	Exon 90 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.25661G>A	p.Arg8554His	missense	Exon 88 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000165 AC: 25 AN: 151866 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.0000708 AC: 17 AN: 240094 AF XY: 0.0000692

Gnomad AFR exome AF: 0.000457

Gnomad AMR exome AF: 0.0000306

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000364

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.000101 AC: 146 AN: 1449956 Hom.: 0 Cov.: 33 AF XY: 0.0000986 AC XY: 71 AN XY: 720216

African (AFR) AF: 0.000427 AC: 14 AN: 32796

American (AMR) AF: 0.0000467 AC: 2 AN: 42836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25646

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39586

South Asian (SAS) AF: 0.0000715 AC: 6 AN: 83954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5542

European-Non Finnish (NFE) AF: 0.000106 AC: 117 AN: 1106610

Other (OTH) AF: 0.000100 AC: 6 AN: 59770

GnomAD4 genome AF: 0.000178 AC: 27 AN: 151984 Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10 AN XY: 74290

African (AFR) AF: 0.000434 AC: 18 AN: 41444

American (AMR) AF: 0.000131 AC: 2 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10532

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

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67970

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.000140 Hom.: 0

Bravo AF: 0.000238

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000543 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000828 AC: 10

EpiCase AF: 0.000109

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not specified (1)
-	1	-	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	14
DANN	Benign	0.89
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.32
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.060
Sift	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.055
MPC		0.10
ClinPred		0.035	T
GERP RS		1.4
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs144587343; hg19: chr2-179579976; COSMIC: COSV100597757; COSMIC: COSV100597757;