rs12621078

Variant names:

• chr2-178558372-A-G
• rs12621078
• NM_001267550.2:c.87087T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001267550.2(TTN):​c.87087T>C​(p.Leu29029Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 1,613,474 control chromosomes in the GnomAD database, including 520 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (50 hom., cov: 33)
  • Exomes 𝑓: 0.023 (470 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 0.234
• Publications: 6 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]

ENSG00000279598 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 2-178558372-A-G is Benign according to our data. Variant chr2-178558372-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.234 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0552 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.87087T>C	p.Leu29029Leu	synonymous	Exon 327 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.82164T>C	p.Leu27388Leu	synonymous	Exon 277 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.79383T>C	p.Leu26461Leu	synonymous	Exon 276 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.87087T>C	p.Leu29029Leu	synonymous	Exon 327 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.86931T>C	p.Leu28977Leu	synonymous	Exon 325 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.86811T>C	p.Leu28937Leu	synonymous	Exon 325 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0203 AC: 3085 AN: 152220 Hom.: 50 Cov.: 33

Gnomad AFR AF: 0.00453

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0220

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.0606

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.0447

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0234

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0259 AC: 6427 AN: 248038 AF XY: 0.0245

Gnomad AFR exome AF: 0.00492

Gnomad AMR exome AF: 0.0335

Gnomad ASJ exome AF: 0.0142

Gnomad EAS exome AF: 0.0615

Gnomad FIN exome AF: 0.0470

Gnomad NFE exome AF: 0.0232

Gnomad OTH exome AF: 0.0256

GnomAD4 exome AF: 0.0232 AC: 33903 AN: 1461136 Hom.: 470 Cov.: 32 AF XY: 0.0228 AC XY: 16580 AN XY: 726798

African (AFR) AF: 0.00409 AC: 137 AN: 33464

American (AMR) AF: 0.0318 AC: 1419 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.0143 AC: 374 AN: 26130

East Asian (EAS) AF: 0.0617 AC: 2441 AN: 39570

South Asian (SAS) AF: 0.00679 AC: 585 AN: 86172

European-Finnish (FIN) AF: 0.0483 AC: 2577 AN: 53360

Middle Eastern (MID) AF: 0.0101 AC: 58 AN: 5764

European-Non Finnish (NFE) AF: 0.0225 AC: 24998 AN: 1111672

Other (OTH) AF: 0.0218 AC: 1314 AN: 60346

GnomAD4 genome AF: 0.0202 AC: 3082 AN: 152338 Hom.: 50 Cov.: 33 AF XY: 0.0207 AC XY: 1544 AN XY: 74486

African (AFR) AF: 0.00452 AC: 188 AN: 41588

American (AMR) AF: 0.0220 AC: 336 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3468

East Asian (EAS) AF: 0.0608 AC: 315 AN: 5184

South Asian (SAS) AF: 0.00766 AC: 37 AN: 4832

European-Finnish (FIN) AF: 0.0447 AC: 475 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0234 AC: 1594 AN: 68028

Other (OTH) AF: 0.0194 AC: 41 AN: 2116

Alfa AF: 0.0233 Hom.: 91

Bravo AF: 0.0186

Asia WGS AF: 0.0280 AC: 96 AN: 3478

EpiCase AF: 0.0203

EpiControl AF: 0.0217

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	3	not provided (3)
-	-	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	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
BayesDel_noAF	Benign	-0.66
CADD	Benign	11
DANN	Benign	0.61
PhyloP100		0.23
Mutation Taster		=99/1	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: rs12621078; hg19: chr2-179423099; COSMIC: COSV60085041;