rs149748934

chr2-178748452-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_133379.5(TTN):c.13948C>T(p.Pro4650Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,612,962 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4650R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (11 hom.)
• Consequence: TTN NM_133379.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: -1.06

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030308366).
• BP6: Variant 2-178748452-G-A is Benign according to our data. Variant chr2-178748452-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47765.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=1}. Variant chr2-178748452-G-A is described in Lovd as [Benign]. Variant chr2-178748452-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00233 (354/151998) while in subpopulation NFE AF= 0.0038 (258/67898). AF 95% confidence interval is 0.00342. There are 0 homozygotes in gnomad4. There are 165 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_133379.5	c.13948C>T	p.Pro4650Ser	missense_variant	46/46	ENST00000360870.10
TTN	NM_001267550.2	c.11311+4672C>T		intron_variant		ENST00000589042.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000360870.10	c.13948C>T	p.Pro4650Ser	missense_variant	46/46	5	NM_133379.5
TTN	ENST00000589042.5	c.11311+4672C>T		intron_variant		5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.1223+5482G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 354 AN: 151880 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00178

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00380

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00198 AC: 493 AN: 248742 Hom.: 1 AF XY: 0.00195 AC XY: 262 AN XY: 134686

Gnomad AFR exome AF: 0.000754

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00350

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00350 AC: 5113 AN: 1460964 Hom.: 11 Cov.: 35 AF XY: 0.00339 AC XY: 2461 AN XY: 726798

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.000712

Gnomad4 NFE exome AF: 0.00431

Gnomad4 OTH exome AF: 0.00237

GnomAD4 genome AF: 0.00233 AC: 354 AN: 151998 Hom.: 0 Cov.: 32 AF XY: 0.00222 AC XY: 165 AN XY: 74308

Gnomad4 AFR AF: 0.000747

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000849

Gnomad4 NFE AF: 0.00380

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00331 Hom.: 2

Bravo AF: 0.00250

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00194 AC: 236

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:7

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	The TTN c.13948C>T; p.Pro4650Ser variant (rs149748934; ClinVar Variation ID: 47765) is rare in the general population (<1% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Pro4650Ser variant cannot be determined with certainty. References: Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. Linke and Hamdani. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
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	GeneDx	Jan 02, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TTN: BP4 -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 10, 2015	p.Pro4650Ser in exon 45A of TTN: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (209/66040) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs149748934). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 06, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Tibial muscular dystrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.44
Dann	Benign	0.34
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PROVEAN	Benign	0.74	N
REVEL	Benign	0.017
Sift	Pathogenic	0.0	D
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.067
MVP		0.040
ClinPred		0.0035	T
GERP RS		-4.2

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: rs149748934; hg19: chr2-179613179;