2-178653325-A-G

Position:

• chr2-178653325-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS1

The NM_001267550.2(TTN):​c.38708-4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 148,882 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0026 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0031 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 splice_region, intron
• Scores: Splicing: ADA: 0.0001705
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -3.93

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 2-178653325-A-G is Benign according to our data. Variant chr2-178653325-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 238764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178653325-A-G is described in Lovd as [Likely_benign]. Variant chr2-178653325-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00264 (393/148882) while in subpopulation SAS AF= 0.00758 (35/4618). AF 95% confidence interval is 0.0056. There are 0 homozygotes in gnomad4. There are 201 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.38708-4T>C		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.38708-4T>C		splice_region_variant, intron_variant		5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 393 AN: 148766 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000533

Gnomad AMI AF: 0.00112

Gnomad AMR AF: 0.00175

Gnomad ASJ AF: 0.00147

Gnomad EAS AF: 0.00379

Gnomad SAS AF: 0.00757

Gnomad FIN AF: 0.00394

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.00361

Gnomad OTH AF: 0.00245

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00310 AC: 4427 AN: 1427846 Hom.: 5 Cov.: 34 AF XY: 0.00315 AC XY: 2235 AN XY: 710422

Gnomad4 AFR exome AF: 0.000391

Gnomad4 AMR exome AF: 0.00339

Gnomad4 ASJ exome AF: 0.00175

Gnomad4 EAS exome AF: 0.00175

Gnomad4 SAS exome AF: 0.00586

Gnomad4 FIN exome AF: 0.00406

Gnomad4 NFE exome AF: 0.00304

Gnomad4 OTH exome AF: 0.00221

GnomAD4 genome AF: 0.00264 AC: 393 AN: 148882 Hom.: 0 Cov.: 29 AF XY: 0.00277 AC XY: 201 AN XY: 72674

Gnomad4 AFR AF: 0.000532

Gnomad4 AMR AF: 0.00175

Gnomad4 ASJ AF: 0.00147

Gnomad4 EAS AF: 0.00381

Gnomad4 SAS AF: 0.00758

Gnomad4 FIN AF: 0.00394

Gnomad4 NFE AF: 0.00361

Gnomad4 OTH AF: 0.00242

Alfa AF: 0.00578 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	TTN: BP4 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 15, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2015	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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 29, 2023	- -

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

Feb 01, 2024

- -

Early-onset myopathy with fatal cardiomyopathy 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

- -

Myopathy, myofibrillar, 9, with early respiratory failure 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
BayesDel_noAF	Benign	-0.45
CADD	Benign	2.2
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.10		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: rs200819643; hg19: chr2-179518052; COSMIC: COSV60438953; COSMIC: COSV60438953;