chr2-178702671-A-C

Position:

• chr2-178702671-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.30224-8T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,607,802 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (42 hom.)
• Consequence: TTN NM_001267550.2 splice_region, intron
• Scores: Splicing: ADA: 0.005304
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 1.44

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 2-178702671-A-C is Benign according to our data. Variant chr2-178702671-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 46830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178702671-A-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00144 (219/152348) while in subpopulation SAS AF= 0.0157 (76/4830). AF 95% confidence interval is 0.0129. There are 1 homozygotes in gnomad4. There are 125 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 42 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.30224-8T>G		splice_region_variant, intron_variant		ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.30224-8T>G		splice_region_variant, intron_variant		5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0155

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00373 AC: 921 AN: 246738 Hom.: 16 AF XY: 0.00452 AC XY: 605 AN XY: 133754

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0177

Gnomad FIN exome AF: 0.0000933

Gnomad NFE exome AF: 0.00137

Gnomad OTH exome AF: 0.00368

GnomAD4 exome AF: 0.00215 AC: 3125 AN: 1455454 Hom.: 42 Cov.: 31 AF XY: 0.00264 AC XY: 1906 AN XY: 722672

Gnomad4 AFR exome AF: 0.000300

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.0170

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0169

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000831

Gnomad4 OTH exome AF: 0.00263

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152348 Hom.: 1 Cov.: 32 AF XY: 0.00168 AC XY: 125 AN XY: 74504

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0157

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00252 Hom.: 2

Bravo AF: 0.00111

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 11, 2015	c.26492-8T>G in intron 103 of TTN: This variant is not expected to have clinical significance because it has been identified in 1.9% (288/15254) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs72650010). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 16, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:2

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Early-onset myopathy with fatal cardiomyopathy Benign:2

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Tibial muscular dystrophy Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Myopathy, myofibrillar, 9, with early respiratory failure Benign:2

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. -
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

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Nov 24, 2017

- -

Dilated cardiomyopathy 1G Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.3
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0053
dbscSNV1_RF	Benign	0.39
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

Other links and lift over

dbSNP: rs72650010; hg19: chr2-179567398;