rs13388274

Positions:

chr2-178769665-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001267550.2(TTN):c.8902+14T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 993,936 control chromosomes in the GnomAD database, including 21 homozygotes. 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 0.0017 ( 1 hom., cov: 6)

Exomes 𝑓: 0.0022 ( 20 hom. )

Consequence

TTN
NM_001267550.2 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:12

Conservation

PhyloP100: -0.162

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 made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 2-178769665-A-T is Benign according to our data. Variant chr2-178769665-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 137827.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=6, Uncertain_significance=4}. Variant chr2-178769665-A-T is described in Lovd as [Benign]. Variant chr2-178769665-A-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0017 (109/64022) while in subpopulation EAS AF= 0.0333 (30/902). AF 95% confidence interval is 0.0239. There are 1 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 6. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 20 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.8902+14T>A		intron_variant		ENST00000589042.5
TTN	NM_133379.5 linkuse as main transcript	c.8902+14T>A		intron_variant		ENST00000360870.10

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
TTN	ENST00000360870.10 linkuse as main transcript	c.8902+14T>A	intron_variant	5	NM_133379.5		Q8WZ42-6
TTN	ENST00000589042.5 linkuse as main transcript	c.8902+14T>A	intron_variant	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.1593-3610A>T	intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00169

AC:

108

AN:

63966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00395

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000442

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0333

Gnomad SAS

AF:

0.00291

Gnomad FIN

AF:

0.000198

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000285

Gnomad OTH

AF:

0.00113

GnomAD3 exomes

AF:

0.0237

AC:

4653

AN:

196464

Hom.:

230

AF XY:

0.0241

AC XY:

2594

AN XY:

107600

show subpopulations

Gnomad AFR exome

AF:

0.0381

Gnomad AMR exome

AF:

0.0142

Gnomad ASJ exome

AF:

0.00707

Gnomad EAS exome

AF:

0.0903

Gnomad SAS exome

AF:

0.0269

Gnomad FIN exome

AF:

0.0132

Gnomad NFE exome

AF:

0.0213

Gnomad OTH exome

AF:

0.0133

GnomAD4 exome

AF:

0.00221

AC:

2059

AN:

929914

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

1025

AN XY:

466546

show subpopulations

Gnomad4 AFR exome

AF:

0.00592

Gnomad4 AMR exome

AF:

0.000930

Gnomad4 ASJ exome

AF:

0.000439

Gnomad4 EAS exome

AF:

0.0399

Gnomad4 SAS exome

AF:

0.00565

Gnomad4 FIN exome

AF:

0.000530

Gnomad4 NFE exome

AF:

0.00149

Gnomad4 OTH exome

AF:

0.00188

GnomAD4 genome

AF:

0.00170

AC:

109

AN:

64022

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

AN XY:

31322

show subpopulations

Gnomad4 AFR

AF:

0.00394

Gnomad4 AMR

AF:

0.000441

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0333

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.000198

Gnomad4 NFE

AF:

0.000285

Gnomad4 OTH

AF:

0.00226

Alfa

AF:

0.00269

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Uncertain:1Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 02, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2J

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Dilated cardiomyopathy 1G

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Early-onset myopathy with fatal cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Myopathy, myofibrillar, 9, with early respiratory failure

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Tibial muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Atrial fibrillation;C0018802:Congestive heart failure;C0042514:Ventricular tachycardia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

May 14, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.3

DANN

Benign

0.60

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