rs6716782

Variant names:

• chr2-178706956-T-G
• rs6716782
• NM_001267550.2:c.29042-2A>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PVS1_Moderate BP6 BS1 BS2

The NM_001267550.2(TTN):​c.29042-2A>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000104 in 1,599,590 control chromosomes in the GnomAD database, including 2 homozygotes. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000059 (2 hom.)
• Consequence: TTN NM_001267550.2 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:9 B:6
• Conservation: PhyloP100: 4.66
• Publications: 5 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 8.613025E-4 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• BP6: Variant 2-178706956-T-G is Benign according to our data. Variant chr2-178706956-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 202355.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000594 (86/1447276) while in subpopulation AFR AF = 0.00237 (78/32940). AF 95% confidence interval is 0.00194. There are 2 homozygotes in GnomAdExome4. There are 41 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.29042-2A>C		splice_acceptor intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.28091-2A>C		splice_acceptor intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.25310-2A>C		splice_acceptor intron	N/A	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.29042-2A>C		splice_acceptor intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.29042-2A>C		splice_acceptor intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.28766-2A>C		splice_acceptor intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000133 AC: 30 AN: 224830 AF XY: 0.0000990

Gnomad AFR exome AF: 0.00182

Gnomad AMR exome AF: 0.0000963

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000991

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000594 AC: 86 AN: 1447276 Hom.: 2 Cov.: 31 AF XY: 0.0000570 AC XY: 41 AN XY: 718702

African (AFR) AF: 0.00237 AC: 78 AN: 32940

American (AMR) AF: 0.000119 AC: 5 AN: 42138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25668

East Asian (EAS) AF: 0.00 AC: 0 AN: 39462

South Asian (SAS) AF: 0.00 AC: 0 AN: 83390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52700

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5716

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105402

Other (OTH) AF: 0.0000167 AC: 1 AN: 59860

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000457 AC XY: 34 AN XY: 74474

African (AFR) AF: 0.00185 AC: 77 AN: 41562

American (AMR) AF: 0.000131 AC: 2 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000271 Hom.: 0

Bravo AF: 0.000635

ESP6500AA AF: 0.00161 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000108 AC: 13

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	6	1	not provided (7)
-	-	2	Cardiomyopathy (2)
-	1	1	not specified (2)
1	1	-	Primary dilated cardiomyopathy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	1	-	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		4.7
GERP RS		6.2
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.94		Position offset: -11
DS_AL_spliceai		1.0		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6716782; hg19: chr2-179571683;