rs587780981

Variant names:

• chr2-178582405-C-T
• rs587780981
• NM_001267550.2:c.66051G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_001267550.2(TTN):​c.66051G>A​(p.Val22017Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,612,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 1.12
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 2-178582405-C-T is Benign according to our data. Variant chr2-178582405-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 137801.
• BP7: Synonymous conserved (PhyloP=1.12 with no splicing effect.

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.66051G>A	p.Val22017Val	synonymous	Exon 314 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.61128G>A	p.Val20376Val	synonymous	Exon 264 of 313	NP_001243779.1
	TTN	NM_133378.4		c.58347G>A	p.Val19449Val	synonymous	Exon 263 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.66051G>A	p.Val22017Val	synonymous	Exon 314 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.65895G>A	p.Val21965Val	synonymous	Exon 312 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.65775G>A	p.Val21925Val	synonymous	Exon 312 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152018 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000246 AC: 61 AN: 247876 AF XY: 0.000230

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000872

Gnomad ASJ exome AF: 0.000798

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.000107 AC: 157 AN: 1460732 Hom.: 0 Cov.: 32 AF XY: 0.0000950 AC XY: 69 AN XY: 726668

African (AFR) AF: 0.0000598 AC: 2 AN: 33424

American (AMR) AF: 0.000761 AC: 34 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.000919 AC: 24 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39512

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5758

European-Non Finnish (NFE) AF: 0.0000594 AC: 66 AN: 1111370

Other (OTH) AF: 0.000381 AC: 23 AN: 60320

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74354

African (AFR) AF: 0.0000241 AC: 1 AN: 41568

American (AMR) AF: 0.000393 AC: 6 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67962

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000166 Hom.: 0

Bravo AF: 0.000264

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	3	not specified (3)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	1.2
DANN	Benign	0.82
PhyloP100		1.1
Mutation Taster		=52/48	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: rs587780981; hg19: chr2-179447132;