rs72648908

Positions:

• chr2-178747646-A-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_133379.5(TTN):​c.14754T>G​(p.Pro4918=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,613,284 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (68 hom.)
• Consequence: TTN NM_133379.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.45

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 2-178747646-A-C is Benign according to our data. Variant chr2-178747646-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 47776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178747646-A-C is described in Lovd as [Benign]. Variant chr2-178747646-A-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.45 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00267 (406/152120) while in subpopulation SAS AF= 0.023 (111/4820). AF 95% confidence interval is 0.0196. There are 3 homozygotes in gnomad4. There are 225 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_133379.5	c.14754T>G	p.Pro4918=	synonymous_variant	46/46	ENST00000360870.10
TTN	NM_001267550.2	c.11311+5478T>G		intron_variant		ENST00000589042.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000360870.10	c.14754T>G	p.Pro4918=	synonymous_variant	46/46	5	NM_133379.5
TTN	ENST00000589042.5	c.11311+5478T>G		intron_variant		5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.1223+4676A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 405 AN: 152002 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00722

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00519 AC: 1299 AN: 250242 Hom.: 20 AF XY: 0.00599 AC XY: 810 AN XY: 135234

Gnomad AFR exome AF: 0.000924

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0230

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00318

Gnomad OTH exome AF: 0.00656

GnomAD4 exome AF: 0.00498 AC: 7283 AN: 1461164 Hom.: 68 Cov.: 34 AF XY: 0.00544 AC XY: 3957 AN XY: 726906

Gnomad4 AFR exome AF: 0.000927

Gnomad4 AMR exome AF: 0.00202

Gnomad4 ASJ exome AF: 0.00973

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0231

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.00395

Gnomad4 OTH exome AF: 0.00600

GnomAD4 genome AF: 0.00267 AC: 406 AN: 152120 Hom.: 3 Cov.: 32 AF XY: 0.00303 AC XY: 225 AN XY: 74374

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00722

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0230

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00309

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00366 Hom.: 3

Bravo AF: 0.00231

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00492

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 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	Jul 24, 2012	Pro4918Pro in Exon 45A of TTN: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence and has been identified in 0.4% (28/7018) of Euro pean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs72648908). -
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	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -

TTN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	9.7
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs72648908; hg19: chr2-179612373; COSMIC: COSV104645336; COSMIC: COSV104645336;