2-178747908-C-T

Variant summary

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

The NM_133379.5(TTN):c.14492G>A(p.Cys4831Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,613,174 control chromosomes in the GnomAD database, including 57 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. C4831C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (50 hom.)
• Consequence: TTN NM_133379.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.703

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023964047).
• BP6: Variant 2-178747908-C-T is Benign according to our data. Variant chr2-178747908-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 47773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178747908-C-T is described in Lovd as [Benign]. Variant chr2-178747908-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00203 (309/152120) while in subpopulation SAS AF= 0.0243 (117/4822). AF 95% confidence interval is 0.0207. There are 7 homozygotes in gnomad4. There are 173 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_133379.5	c.14492G>A	p.Cys4831Tyr	missense_variant	46/46	ENST00000360870.10
TTN	NM_001267550.2	c.11311+5216G>A		intron_variant		ENST00000589042.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000360870.10	c.14492G>A	p.Cys4831Tyr	missense_variant	46/46	5	NM_133379.5
TTN	ENST00000589042.5	c.11311+5216G>A		intron_variant		5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.1223+4938C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00201 AC: 306 AN: 152002 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00204

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00177

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00421 AC: 1052 AN: 250106 Hom.: 14 AF XY: 0.00525 AC XY: 710 AN XY: 135222

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000813

Gnomad ASJ exome AF: 0.00836

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.0223

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00203

Gnomad OTH exome AF: 0.00395

GnomAD4 exome AF: 0.00252 AC: 3678 AN: 1461054 Hom.: 50 Cov.: 35 AF XY: 0.00315 AC XY: 2286 AN XY: 726846

Gnomad4 AFR exome AF: 0.000449

Gnomad4 AMR exome AF: 0.000740

Gnomad4 ASJ exome AF: 0.00782

Gnomad4 EAS exome AF: 0.000177

Gnomad4 SAS exome AF: 0.0214

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00121

Gnomad4 OTH exome AF: 0.00343

GnomAD4 genome AF: 0.00203 AC: 309 AN: 152120 Hom.: 7 Cov.: 32 AF XY: 0.00233 AC XY: 173 AN XY: 74354

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0243

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00177

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00219 Hom.: 2

Bravo AF: 0.00127

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00470 AC: 571

Asia WGS AF: 0.0130 AC: 44 AN: 3476

EpiCase AF: 0.00300

EpiControl AF: 0.00314

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5 Other:1

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 provided, no classification provided	clinical testing	GeneDx	Jul 29, 2014	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TTN: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 12, 2020	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 17, 2014	p.Cys4831Tyr in exon 46 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 2.35% (390/16604) of South Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs150615457). Moreover, cysteine (Cys) at position 4831 is not conser ved in mammals an evolutionarily distant species and opossum, tasmanian devil, wallaby and platypus have a tyrosine (Tyr) at this position. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	6.3
Dann	Benign	0.47
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.071
Sift	Benign	0.16	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.36
MVP		0.10
ClinPred		0.00030	T
GERP RS		-0.046

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: rs150615457; hg19: chr2-179612635;