chr2-178679958-C-CTCT

Position:

• chr2-178679958-C-CTCT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_001267550.2(TTN):​c.33515_33516insAGA​(p.Glu11171dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.0162 in 1,613,012 control chromosomes in the GnomAD database, including 231 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (10 hom., cov: 32)
  • Exomes 𝑓: 0.017 (221 hom.)
• Consequence: TTN NM_001267550.2 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:16
• Conservation: PhyloP100: 3.88

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-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]

LOC124906100 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001267550.2. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 2-178679958-C-CTCT is Benign according to our data. Variant chr2-178679958-C-CTCT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46889.We mark this variant Likely_benign, oryginal submissions are: {Benign=12, Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0111 (1687/152018) while in subpopulation NFE AF= 0.0185 (1258/67912). AF 95% confidence interval is 0.0177. There are 10 homozygotes in gnomad4. There are 750 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.33515_33516insAGA	p.Glu11171dup	inframe_insertion	140/363	ENST00000589042.5	NP_001254479.2
LOC124906100	XR_007087318.1	n.2186-33783_2186-33781dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.33515_33516insAGA	p.Glu11171dup	inframe_insertion	140/363	5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.503-54533_503-54531dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1687 AN: 151900 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00321

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00513

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.00814

GnomAD3 exomes AF: 0.0113 AC: 2798 AN: 248470 Hom.: 22 AF XY: 0.0115 AC XY: 1554 AN XY: 134786

Gnomad AFR exome AF: 0.00356

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.00697

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00533

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.0179

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.0167 AC: 24446 AN: 1460994 Hom.: 221 Cov.: 32 AF XY: 0.0164 AC XY: 11903 AN XY: 726796

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.00452

Gnomad4 ASJ exome AF: 0.00590

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00597

Gnomad4 FIN exome AF: 0.0140

Gnomad4 NFE exome AF: 0.0198

Gnomad4 OTH exome AF: 0.0123

GnomAD4 genome AF: 0.0111 AC: 1687 AN: 152018 Hom.: 10 Cov.: 32 AF XY: 0.0101 AC XY: 750 AN XY: 74328

Gnomad4 AFR AF: 0.00320

Gnomad4 AMR AF: 0.00512

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.0141

Gnomad4 NFE AF: 0.0185

Gnomad4 OTH AF: 0.00806

Bravo AF: 0.0101

EpiCase AF: 0.0164

EpiControl AF: 0.0176

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:16

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 27, 2012	Glu9928dup in exon 137 of TTN: This variant is not expected to have clinical sig nificance because it has been identified in 1.6% (131/7868) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS/). -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 02, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 11, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 26, 2019	Variant summary: TTN c.29781_29783dupAGA (p.Glu9928dup) results in an in-frame duplication in exon 137 of the encoded protein. The variant allele was found at a frequency of 0.011 in 248470 control chromosomes in the gnomAD database, including 22 homozygotes. The observed variant frequency is approximately 18.0 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 benign. To our knowledge, no conclusive occurrence of c.29781_29783dupAGA in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic/likely pathogenic variant(s) have been reported in the literature as well as at our laboratory (example DSP c.939+1G>A (Pugh_2014); TTN c.34782_34785delTTGT, p.Cys11595fs*9, our laboratory), providing supporting evidence for a benign role. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TTN: PM4:Supporting, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -

Ventricular fibrillation, paroxysmal familial, type 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Oct 17, 2013

- -

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

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 10, 2019

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 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. -

Primary dilated cardiomyopathy;C1142166:Brugada syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Dec 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs368327166; hg19: chr2-179544685;