rs17452588

Variant names:

• chr2-178720585-G-A
• rs17452588
• NM_001267550.2:c.23177C>T

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.23177C>T​(p.Ser7726Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00712 in 1,613,202 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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. S7726S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0067 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0072 (65 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:22
• Conservation: PhyloP100: 2.89
• Publications: 14 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=0.0071484745).
• BP6: Variant 2-178720585-G-A is Benign according to our data. Variant chr2-178720585-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46713.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00666 (1013/152176) while in subpopulation NFE AF = 0.00778 (529/67982). AF 95% confidence interval is 0.00723. There are 8 homozygotes in GnomAd4. There are 569 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.23177C>T	p.Ser7726Leu	missense	Exon 80 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.22226C>T	p.Ser7409Leu	missense	Exon 78 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.19445C>T	p.Ser6482Leu	missense	Exon 77 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.23177C>T	p.Ser7726Leu	missense	Exon 80 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.23177C>T	p.Ser7726Leu	missense	Exon 80 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.22901C>T	p.Ser7634Leu	missense	Exon 78 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00666 AC: 1013 AN: 152060 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0294

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00778

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00709 AC: 1757 AN: 247748 AF XY: 0.00682

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00250

Gnomad ASJ exome AF: 0.0121

Gnomad EAS exome AF: 0.0000560

Gnomad FIN exome AF: 0.0302

Gnomad NFE exome AF: 0.00721

Gnomad OTH exome AF: 0.00550

GnomAD4 exome AF: 0.00716 AC: 10467 AN: 1461026 Hom.: 65 Cov.: 35 AF XY: 0.00709 AC XY: 5156 AN XY: 726796

African (AFR) AF: 0.000987 AC: 33 AN: 33428

American (AMR) AF: 0.00242 AC: 108 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 279 AN: 26110

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39652

South Asian (SAS) AF: 0.00150 AC: 129 AN: 86198

European-Finnish (FIN) AF: 0.0268 AC: 1429 AN: 53346

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.00732 AC: 8136 AN: 1111522

Other (OTH) AF: 0.00580 AC: 350 AN: 60334

GnomAD4 genome AF: 0.00666 AC: 1013 AN: 152176 Hom.: 8 Cov.: 33 AF XY: 0.00765 AC XY: 569 AN XY: 74380

African (AFR) AF: 0.00130 AC: 54 AN: 41542

American (AMR) AF: 0.00399 AC: 61 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4820

European-Finnish (FIN) AF: 0.0294 AC: 311 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00778 AC: 529 AN: 67982

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00638 Hom.: 16

Bravo AF: 0.00439

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000554 AC: 2

ESP6500EA AF: 0.00921 AC: 75

ExAC AF: 0.00657 AC: 793

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00600

EpiControl AF: 0.00482

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	4	not provided (4)
-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Benign	0.96
Eigen	Benign	0.023
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.87	T
PhyloP100		2.9
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.20
Sift	Uncertain	0.0090	D
Polyphen		0.031	B
Vest4		0.23
MVP		0.56
MPC		0.076
ClinPred		0.027	T
GERP RS		5.9
Mutation Taster		=93/7	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: rs17452588; hg19: chr2-179585312; COSMIC: COSV59883783; COSMIC: COSV59883783;