2-178647040-GTATA-G

Position:

chr2-178647040-GTATA-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BA1

The NM_001267550.2(TTN):c.40222+20_40222+23del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 714,078 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 21)

Exomes 𝑓: 0.024 ( 0 hom. )

Consequence

TTN
NM_001267550.2 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.346

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:

LOC124906100 (HGNC:):

LOC124906100 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 2-178647040-GTATA-G is Benign according to our data. Variant chr2-178647040-GTATA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191975.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr2-178647040-GTATA-G is described in Lovd as [Benign]. Variant chr2-178647040-GTATA-G is described in Lovd as [Likely_benign]. Variant chr2-178647040-GTATA-G is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0771 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.40222+20_40222+23del		intron_variant		ENST00000589042.5
LOC124906100	XR_007087318.1 linkuse as main transcript	n.2185+2558_2185+2561del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.40222+20_40222+23del		intron_variant		5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.502+49378_502+49381del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000140

AC:

AN:

143182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000758

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000280

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000448

Gnomad FIN

AF:

0.000927

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000309

Gnomad OTH

AF:

0.000514

GnomAD3 exomes

AF:

0.0208

AC:

319

AN:

15314

Hom.:

AF XY:

0.0212

AC XY:

167

AN XY:

7862

show subpopulations

Gnomad AFR exome

AF:

0.126

Gnomad AMR exome

AF:

0.0805

Gnomad ASJ exome

AF:

0.0323

Gnomad EAS exome

AF:

0.00833

Gnomad SAS exome

AF:

0.0699

Gnomad FIN exome

AF:

0.0128

Gnomad NFE exome

AF:

0.0187

Gnomad OTH exome

AF:

0.0392

GnomAD4 exome

AF:

0.0244

AC:

13941

AN:

570836

Hom.:

AF XY:

0.0244

AC XY:

6916

AN XY:

283546

show subpopulations

Gnomad4 AFR exome

AF:

0.0813

Gnomad4 AMR exome

AF:

0.0606

Gnomad4 ASJ exome

AF:

0.0341

Gnomad4 EAS exome

AF:

0.0286

Gnomad4 SAS exome

AF:

0.0376

Gnomad4 FIN exome

AF:

0.0250

Gnomad4 NFE exome

AF:

0.0212

Gnomad4 OTH exome

AF:

0.0322

GnomAD4 genome

AF:

0.000147

AC:

AN:

143242

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

AN XY:

69488

show subpopulations

Gnomad4 AFR

AF:

0.0000756

Gnomad4 AMR

AF:

0.000280

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000450

Gnomad4 FIN

AF:

0.000927

Gnomad4 NFE

AF:

0.0000309

Gnomad4 OTH

AF:

0.00102

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over