2-178713381-TACAAAACAAAACAAA-TACAAAACAAAACAAAACAAAACAAA

Position:

chr2-178713381-TACAAAACAAAACAAA-TACAAAACAAAACAAAACAAAACAAA

Variant summary

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

The NM_001267550.2(TTN):c.26762-10_26762-9insTTTGTTTTGT variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,468,934 control chromosomes in the GnomAD database, including 71 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 42 hom., cov: 24)

Exomes 𝑓: 0.0027 ( 29 hom. )

Consequence

TTN
NM_001267550.2 splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.08

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 -16 ACMG points.

BP6

Variant 2-178713381-T-TACAAAACAAA is Benign according to our data. Variant chr2-178713381-T-TACAAAACAAA is described in ClinVar as [Likely_benign]. Clinvar id is 167796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0142 (2150/150994) while in subpopulation AFR AF= 0.0452 (1854/41010). AF 95% confidence interval is 0.0435. There are 42 homozygotes in gnomad4. There are 971 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 42 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.26762-10_26762-9insTTTGTTTTGT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000589042.5	NP_001254479.2
LOC124906100	XR_007087318.1 linkuse as main transcript	n.2186-351_2186-342dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.26762-10_26762-9insTTTGTTTTGT		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.503-21101_503-21092dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0141

AC:

2129

AN:

150878

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0448

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00700

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00276

Gnomad SAS

AF:

0.00169

Gnomad FIN

AF:

0.000763

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.00198

Gnomad OTH

AF:

0.0116

GnomAD3 exomes

AF:

0.00456

AC:

458

AN:

100440

Hom.:

AF XY:

0.00376

AC XY:

192

AN XY:

51018

show subpopulations

Gnomad AFR exome

AF:

0.0411

Gnomad AMR exome

AF:

0.00459

Gnomad ASJ exome

AF:

0.000479

Gnomad EAS exome

AF:

0.00231

Gnomad SAS exome

AF:

0.000951

Gnomad FIN exome

AF:

0.00104

Gnomad NFE exome

AF:

0.00134

Gnomad OTH exome

AF:

0.00107

GnomAD4 exome

AF:

0.00270

AC:

3562

AN:

1317940

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

1636

AN XY:

641860

show subpopulations

Gnomad4 AFR exome

AF:

0.0413

Gnomad4 AMR exome

AF:

0.00572

Gnomad4 ASJ exome

AF:

0.000283

Gnomad4 EAS exome

AF:

0.00216

Gnomad4 SAS exome

AF:

0.00128

Gnomad4 FIN exome

AF:

0.00158

Gnomad4 NFE exome

AF:

0.00170

Gnomad4 OTH exome

AF:

0.00427

GnomAD4 genome

AF:

0.0142

AC:

2150

AN:

150994

Hom.:

Cov.:

AF XY:

0.0132

AC XY:

971

AN XY:

73698

show subpopulations

Gnomad4 AFR

AF:

0.0452

Gnomad4 AMR

AF:

0.00699

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00277

Gnomad4 SAS

AF:

0.00169

Gnomad4 FIN

AF:

0.000763

Gnomad4 NFE

AF:

0.00198

Gnomad4 OTH

AF:

0.0114

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 25, 2015	c.23030-39TTTGT[8] in intron 89 of TTN: This variant is part of a 5 bp repeat (T TTGT) and adds 2 repeat units to 6 present in the reference sequence. It is not expected to have clinical significance because it has been identified in 3.9% (8 2/2118) of African chromosomes (ExAC, http://exac.broadinstitute.org; dbSNP rs71 393436). Although this variant is located in the splice region, computational to ols do not predict an effect. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2019	Variant summary: TTN c.23030-19_23030-10dup10 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. 5/5 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 0.0069 in 131482 control chromosomes, predominantly at a frequency of 0.043 within the African or African-American subpopulation in the gnomAD database, including 12 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 69-folds over 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. Five ClinVar submissions (evaluation after 2014) cites the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -

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

Feb 01, 2024

- -

Limb-girdle muscular dystrophy, recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jan 23, 2020

- -

Early-onset myopathy with fatal cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated Cardiomyopathy, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 26, 2020

- -

Tibial muscular dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Myopathy, myofibrillar, 9, with early respiratory failure

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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