rs139512154

chr2-178650214-TTTTCCTCTTCAGGAGCAA-Tchr2-178650214-TTTTCCTCTTCAGGAGCAA-TTTTCCTCTTCAGGAGCAATTTCCTCTTCAGGAGCAA

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBA1

The NM_001267550.2(TTN):c.39749_39766del(p.Ile13250_Glu13255del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,596,062 control chromosomes in the GnomAD database, including 290 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 120 hom., cov: 32)

Exomes 𝑓: 0.010 ( 170 hom. )

Consequence

TTN
NM_001267550.2 inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.41

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 -14 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001267550.2.

BP6

Variant 2-178650214-TTTTCCTCTTCAGGAGCAA-T is Benign according to our data. Variant chr2-178650214-TTTTCCTCTTCAGGAGCAA-T is described in ClinVar as [Likely_benign]. Clinvar id is 46932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178650214-TTTTCCTCTTCAGGAGCAA-T is described in Lovd as [Benign]. Variant chr2-178650214-TTTTCCTCTTCAGGAGCAA-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0664 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.39749_39766del	p.Ile13250_Glu13255del	inframe_deletion	210/363	ENST00000589042.5
LOC124906100	XR_007087318.1 linkuse as main transcript	n.2185+5739_2185+5756del		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.39749_39766del	p.Ile13250_Glu13255del	inframe_deletion	210/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.502+52559_502+52576del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0281

AC:

4273

AN:

152052

Hom.:

120

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0684

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0257

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.00773

Gnomad SAS

AF:

0.0178

Gnomad FIN

AF:

0.0180

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00919

Gnomad OTH

AF:

0.0287

GnomAD3 exomes

AF:

0.0105

AC:

2340

AN:

223830

Hom.:

AF XY:

0.0102

AC XY:

1227

AN XY:

120592

show subpopulations

Gnomad AFR exome

AF:

0.0460

Gnomad AMR exome

AF:

0.00777

Gnomad ASJ exome

AF:

0.00751

Gnomad EAS exome

AF:

0.00448

Gnomad SAS exome

AF:

0.0136

Gnomad FIN exome

AF:

0.0134

Gnomad NFE exome

AF:

0.00650

Gnomad OTH exome

AF:

0.00951

GnomAD4 exome

AF:

0.0102

AC:

14719

AN:

1443892

Hom.:

170

AF XY:

0.0104

AC XY:

7416

AN XY:

716464

show subpopulations

Gnomad4 AFR exome

AF:

0.0564

Gnomad4 AMR exome

AF:

0.0104

Gnomad4 ASJ exome

AF:

0.00934

Gnomad4 EAS exome

AF:

0.00294

Gnomad4 SAS exome

AF:

0.0170

Gnomad4 FIN exome

AF:

0.0147

Gnomad4 NFE exome

AF:

0.00806

Gnomad4 OTH exome

AF:

0.0145

GnomAD4 genome

AF:

0.0281

AC:

4283

AN:

152170

Hom.:

120

Cov.:

AF XY:

0.0284

AC XY:

2112

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0685

Gnomad4 AMR

AF:

0.0256

Gnomad4 ASJ

AF:

0.00980

Gnomad4 EAS

AF:

0.00756

Gnomad4 SAS

AF:

0.0174

Gnomad4 FIN

AF:

0.0180

Gnomad4 NFE

AF:

0.00919

Gnomad4 OTH

AF:

0.0284

Alfa

AF:

0.00600

Hom.:

Bravo

AF:

0.0297

Asia WGS

AF:

0.0140

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 23, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 27, 2012	Ile10816_Glu10821del in intron 164 of TTN: This variant is not expected to have clinical significance because it has been identified in 11.0% (21/192) of Luhya (Kenyan) chromosomes from a broad population by the 1000 Genomes project (dbSNP rs139512154). -
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	Nov 18, 2019	Variant summary: TTN c.32447_32464del18 (p.Ile10816_Glu10821del) results in an in-frame deletion that is predicted to remove six amino acids from the encoded protein. The variant allele was found at a frequency of 0.01 in 223830 control chromosomes in the gnomAD database, including 33 homozygotes. The observed variant frequency is approximately 17 fold the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is benign. Five ClinVar submitters (evaluation after 2014) have cited the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Nov 29, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 02, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 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

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Dec 17, 2015

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2013

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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