rs201184203

chr2-178664094-G-Achr2-178664094-G-Cchr2-178664094-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001267550.2(TTN):c.36285C>T(p.His12095=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,608,628 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.466

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-178664094-G-A is Benign according to our data. Variant chr2-178664094-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 238752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178664094-G-A is described in Lovd as [Benign]. Variant chr2-178664094-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.466 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.36285C>T	p.His12095=	synonymous_variant	169/363	ENST00000589042.5
LOC124906100	XR_007087318.1	n.2185+19593G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.36285C>T	p.His12095=	synonymous_variant	169/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.502+66413G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 151286 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000365

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000264

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00443

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00243

Gnomad OTH AF: 0.000962

GnomAD3 exomes AF: 0.00131 AC: 313 AN: 239722 Hom.: 0 AF XY: 0.00141 AC XY: 185 AN XY: 131448

Gnomad AFR exome AF: 0.000209

Gnomad AMR exome AF: 0.000419

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.0000571

Gnomad SAS exome AF: 0.00205

Gnomad FIN exome AF: 0.000281

Gnomad NFE exome AF: 0.00208

Gnomad OTH exome AF: 0.000343

GnomAD4 exome AF: 0.00188 AC: 2734 AN: 1457222 Hom.: 3 Cov.: 33 AF XY: 0.00191 AC XY: 1388 AN XY: 724972

Gnomad4 AFR exome AF: 0.000242

Gnomad4 AMR exome AF: 0.000412

Gnomad4 ASJ exome AF: 0.000232

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00235

Gnomad4 FIN exome AF: 0.000303

Gnomad4 NFE exome AF: 0.00216

Gnomad4 OTH exome AF: 0.00140

GnomAD4 genome AF: 0.00139 AC: 211 AN: 151406 Hom.: 0 Cov.: 31 AF XY: 0.00133 AC XY: 98 AN XY: 73946

Gnomad4 AFR AF: 0.000364

Gnomad4 AMR AF: 0.000263

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00443

Gnomad4 FIN AF: 0.000284

Gnomad4 NFE AF: 0.00243

Gnomad4 OTH AF: 0.000952

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.00125

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00197

EpiControl AF: 0.00178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TTN: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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

Invitae

Jan 31, 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	-0.83
Cadd	Benign	0.088
Dann	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs201184203; hg19: chr2-179528821;