rs79406408

Variant names:

• chr2-178578948-G-A
• rs79406408
• NM_001267550.2:c.68082C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_001267550.2(TTN):​c.68082C>T​(p.Cys22694Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00033 in 1,613,182 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 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:8
• Conservation: PhyloP100: 1.37
• Publications: 2 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]

ENSG00000270574 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 2-178578948-G-A is Benign according to our data. Variant chr2-178578948-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178197.
• BP7: Synonymous conserved (PhyloP=1.37 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000333 (486/1461120) while in subpopulation EAS AF = 0.00455 (180/39592). AF 95% confidence interval is 0.004. There are 0 homozygotes in GnomAdExome4. There are 218 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

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.68082C>T	p.Cys22694Cys	synonymous	Exon 320 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.63159C>T	p.Cys21053Cys	synonymous	Exon 270 of 313	NP_001243779.1
	TTN	NM_133378.4		c.60378C>T	p.Cys20126Cys	synonymous	Exon 269 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.68082C>T	p.Cys22694Cys	synonymous	Exon 320 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.67926C>T	p.Cys22642Cys	synonymous	Exon 318 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.67806C>T	p.Cys22602Cys	synonymous	Exon 318 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000257 AC: 39 AN: 151944 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00233

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000213 AC: 53 AN: 248462 AF XY: 0.000215

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00134

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000169

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000333 AC: 486 AN: 1461120 Hom.: 0 Cov.: 33 AF XY: 0.000300 AC XY: 218 AN XY: 726846

African (AFR) AF: 0.000718 AC: 24 AN: 33442

American (AMR) AF: 0.0000671 AC: 3 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00455 AC: 180 AN: 39592

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000231 AC: 257 AN: 1111522

Other (OTH) AF: 0.000331 AC: 20 AN: 60338

GnomAD4 genome AF: 0.000303 AC: 46 AN: 152062 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74318

African (AFR) AF: 0.000554 AC: 23 AN: 41498

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00234 AC: 12 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67966

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

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000257

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	2	not specified (2)
-	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	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Benign	0.82
PhyloP100		1.4
Mutation Taster		=90/10	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: rs79406408; hg19: chr2-179443675; COSMIC: COSV60282590;