rs56018860

Variant names:

• chr2-178568494-T-C
• rs56018860
• NM_001267550.2:c.77638A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.77638A>G​(p.Thr25880Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 1,613,398 control chromosomes in the GnomAD database, including 526 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T25880I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (51 hom., cov: 33)
  • Exomes 𝑓: 0.023 (475 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 0.742
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001907289).
• BP6: Variant 2-178568494-T-C is Benign according to our data. Variant chr2-178568494-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0561 is higher than 0.05.

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.77638A>G	p.Thr25880Ala	missense	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.72715A>G	p.Thr24239Ala	missense	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.69934A>G	p.Thr23312Ala	missense	Exon 275 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.77638A>G	p.Thr25880Ala	missense	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.77482A>G	p.Thr25828Ala	missense	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.77362A>G	p.Thr25788Ala	missense	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3076 AN: 152058 Hom.: 51 Cov.: 33

Gnomad AFR AF: 0.00449

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0217

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.0616

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.0447

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0234

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0260 AC: 6458 AN: 248186 AF XY: 0.0246

Gnomad AFR exome AF: 0.00491

Gnomad AMR exome AF: 0.0338

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.0617

Gnomad FIN exome AF: 0.0472

Gnomad NFE exome AF: 0.0233

Gnomad OTH exome AF: 0.0259

GnomAD4 exome AF: 0.0232 AC: 33842 AN: 1461222 Hom.: 475 Cov.: 41 AF XY: 0.0228 AC XY: 16561 AN XY: 726894

African (AFR) AF: 0.00404 AC: 135 AN: 33456

American (AMR) AF: 0.0320 AC: 1429 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0143 AC: 374 AN: 26118

East Asian (EAS) AF: 0.0634 AC: 2513 AN: 39624

South Asian (SAS) AF: 0.00669 AC: 577 AN: 86246

European-Finnish (FIN) AF: 0.0483 AC: 2578 AN: 53380

Middle Eastern (MID) AF: 0.00990 AC: 57 AN: 5760

European-Non Finnish (NFE) AF: 0.0224 AC: 24866 AN: 1111590

Other (OTH) AF: 0.0218 AC: 1313 AN: 60346

GnomAD4 genome AF: 0.0202 AC: 3073 AN: 152176 Hom.: 51 Cov.: 33 AF XY: 0.0207 AC XY: 1537 AN XY: 74382

African (AFR) AF: 0.00448 AC: 186 AN: 41562

American (AMR) AF: 0.0216 AC: 330 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3470

East Asian (EAS) AF: 0.0617 AC: 318 AN: 5152

South Asian (SAS) AF: 0.00767 AC: 37 AN: 4824

European-Finnish (FIN) AF: 0.0447 AC: 474 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0234 AC: 1591 AN: 67982

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.0230 Hom.: 172

Bravo AF: 0.0185

TwinsUK AF: 0.0262 AC: 97

ALSPAC AF: 0.0244 AC: 94

ESP6500AA AF: 0.00569 AC: 22

ESP6500EA AF: 0.0209 AC: 173

ExAC AF: 0.0261 AC: 3153

Asia WGS AF: 0.0280 AC: 96 AN: 3476

EpiCase AF: 0.0202

EpiControl AF: 0.0218

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Benign	0.79
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.74
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.12
Sift	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.14
MPC		0.082
ClinPred		0.0049	T
GERP RS		-1.1
Mutation Taster		=96/4	polymorphism (auto)

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: rs56018860; hg19: chr2-179433221; COSMIC: COSV60085185;