2-178722141-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001267550.2(TTN):c.22529-7C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000583 in 1,544,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000057 ( 0 hom. )

Consequence

TTN
NM_001267550.2 splice_region, intron

Scores

Splicing: ADA: 0.002175

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.247

Publications

0 publications found

Variant links:

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 links:

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]

TTN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 2-178722141-G-T is Benign according to our data. Variant chr2-178722141-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 466907.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TTN	NM_001267550.2	MANE Select	c.22529-7C>A	splice_region intron	N/A	NP_001254479.2
TTN	NM_001256850.1		c.21578-7C>A	splice_region intron	N/A	NP_001243779.1
TTN	NM_133378.4		c.18797-7C>A	splice_region intron	N/A	NP_596869.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TTN	ENST00000589042.5	TSL:5 MANE Select	c.22529-7C>A	splice_region intron	N/A	ENSP00000467141.1
TTN	ENST00000446966.2	TSL:1	c.22529-7C>A	splice_region intron	N/A	ENSP00000408004.2
TTN	ENST00000436599.2	TSL:1	c.22253-7C>A	splice_region intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD2 exomes

AF:

0.0000104

AC:

AN:

191702

AF XY:

0.00000974

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000214

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000575

AC:

AN:

1392302

Hom.:

Cov.:

AF XY:

0.00000583

AC XY:

AN XY:

685706

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30774

American (AMR)

AF:

0.00

AC:

AN:

33008

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21784

East Asian (EAS)

AF:

0.00

AC:

AN:

39136

South Asian (SAS)

AF:

0.00

AC:

AN:

73018

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50834

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5418

European-Non Finnish (NFE)

AF:

0.00000740

AC:

AN:

1081008

Other (OTH)

AF:

0.00

AC:

AN:

57322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G

Uncertain:1

Jun 14, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Apr 04, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

9.1

(source)

DANN

Benign

0.46

PhyloP100

0.25

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0022

dbscSNV1_RF

Benign

0.12

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.24

Position offset: -7

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over