2-178766630-TAAA-TAA

Position:

chr2-178766630-TAAA-TAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001267550.2(TTN):c.9472-19delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000624 in 1,593,290 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 3 hom. )

Consequence

TTN
NM_001267550.2 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.44

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:):

TTN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 2-178766630-TA-T is Benign according to our data. Variant chr2-178766630-TA-T is described in ClinVar as [Benign]. Clinvar id is 202287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178766630-TA-T is described in Lovd as [Benign]. Variant chr2-178766630-TA-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.002 (302/151050) while in subpopulation AFR AF= 0.00583 (240/41184). AF 95% confidence interval is 0.00522. There are 1 homozygotes in gnomad4. There are 132 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.9472-19delT		intron_variant		ENST00000589042.5	NP_001254479.2	A0A0A0MTS7
TTN	NM_133379.5 linkuse as main transcript	c.9472-19delT		intron_variant		ENST00000360870.10	NP_596870.2	Q8WZ42-6Q7Z3B7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.9472-19delT		intron_variant		5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7
TTN	ENST00000360870.10 linkuse as main transcript	c.9472-19delT		intron_variant		5	NM_133379.5	ENSP00000354117.4		Q8WZ42-6

Frequencies

GnomAD3 genomes

AF:

0.00200

AC:

302

AN:

150948

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00584

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00155

Gnomad ASJ

AF:

0.00606

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00108

Gnomad FIN

AF:

0.0000949

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00101

AC:

247

AN:

244338

Hom.:

AF XY:

0.000854

AC XY:

113

AN XY:

132322

show subpopulations

Gnomad AFR exome

AF:

0.00632

Gnomad AMR exome

AF:

0.000825

Gnomad ASJ exome

AF:

0.00541

Gnomad EAS exome

AF:

0.000276

Gnomad SAS exome

AF:

0.00113

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000180

Gnomad OTH exome

AF:

0.00117

GnomAD4 exome

AF:

0.000481

AC:

693

AN:

1442240

Hom.:

Cov.:

AF XY:

0.000473

AC XY:

340

AN XY:

718716

show subpopulations

Gnomad4 AFR exome

AF:

0.00626

Gnomad4 AMR exome

AF:

0.000808

Gnomad4 ASJ exome

AF:

0.00435

Gnomad4 EAS exome

AF:

0.000406

Gnomad4 SAS exome

AF:

0.000851

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.000162

Gnomad4 OTH exome

AF:

0.00110

GnomAD4 genome

AF:

0.00200

AC:

302

AN:

151050

Hom.:

Cov.:

AF XY:

0.00179

AC XY:

132

AN XY:

73730

show subpopulations

Gnomad4 AFR

AF:

0.00583

Gnomad4 AMR

AF:

0.00155

Gnomad4 ASJ

AF:

0.00606

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00108

Gnomad4 FIN

AF:

0.0000949

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00142

Bravo

AF:

0.00222

Asia WGS

AF:

0.000877

AC:

AN:

3436

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2014	The variant is found in CARDIOMYOPATHY,DCM-CRDM panel(s). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 13, 2020	Variant summary: TTN c.9472-19delT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.001 in 244338 control chromosomes, predominantly at a frequency of 0.0063 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.9472-19delT in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

Autosomal recessive limb-girdle muscular dystrophy type 2J

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Early-onset myopathy with fatal cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

- -

Myopathy, myofibrillar, 9, with early respiratory failure

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Tibial muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

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