rs72677226

Variant names:

• chr2-178620850-T-A
• rs72677226
• NM_001267550.2:c.45760A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178620850-T-A
• chr2-178620850-T-C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001267550.2(TTN):​c.45760A>T​(p.Ile15254Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,612,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. I15254I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 1.56
• Publications: 1 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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13110197).
• BP6: Variant 2-178620850-T-A is Benign according to our data. Variant chr2-178620850-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 288762.

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.45760A>T	p.Ile15254Phe	missense	Exon 247 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.40837A>T	p.Ile13613Phe	missense	Exon 197 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.38056A>T	p.Ile12686Phe	missense	Exon 196 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.45760A>T	p.Ile15254Phe	missense	Exon 247 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.45604A>T	p.Ile15202Phe	missense	Exon 245 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.45484A>T	p.Ile15162Phe	missense	Exon 245 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151906 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000121 AC: 30 AN: 247526 AF XY: 0.0000819

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.000843

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000240 AC: 35 AN: 1460636 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 726626

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.000717 AC: 32 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

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: 0.00 AC: 0 AN: 1111244

Other (OTH) AF: 0.0000497 AC: 3 AN: 60302

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151906 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74194

African (AFR) AF: 0.0000483 AC: 2 AN: 41390

American (AMR) AF: 0.000197 AC: 3 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67906

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.000116 AC: 14

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Benign	0.86
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.25
Sift	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.44
MutPred		0.44		Gain of ubiquitination at K13617 (P = 0.0707)
MVP		0.71
MPC		0.44
ClinPred		0.076	T
GERP RS		5.8
Mutation Taster		=83/17	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: rs72677226; hg19: chr2-179485577;