rs200513156

Positions:

• chr2-178664032-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.36347A>G​(p.Glu12116Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,613,386 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0032 (13 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.496

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 -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TTN. . Gene score misZ -1.1021 (greater than the threshold 3.09). Trascript score misZ 6.9794 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, tibial muscular dystrophy, early-onset myopathy with fatal cardiomyopathy, autosomal recessive centronuclear myopathy, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 9, TTN-related myopathy, dilated cardiomyopathy 1G, arrhythmogenic right ventricular cardiomyopathy, myopathy, myofibrillar, 9, with early respiratory failure, familial isolated dilated cardiomyopathy, childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome, autosomal recessive limb-girdle muscular dystrophy type 2J.
• BP4: Computational evidence support a benign effect (MetaRNN=0.006957084).
• BP6: Variant 2-178664032-T-C is Benign according to our data. Variant chr2-178664032-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 192216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178664032-T-C is described in Lovd as [Benign]. Variant chr2-178664032-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00206 (313/152278) while in subpopulation NFE AF= 0.00379 (258/68008). AF 95% confidence interval is 0.00341. There are 0 homozygotes in gnomad4. There are 117 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.36347A>G	p.Glu12116Gly	missense_variant	169/363	ENST00000589042.5	NP_001254479.2
LOC124906100	XR_007087318.1	n.2185+19531T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.36347A>G	p.Glu12116Gly	missense_variant	169/363	5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.502+66351T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 313 AN: 152160 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00379

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00190 AC: 463 AN: 244288 Hom.: 0 AF XY: 0.00188 AC XY: 251 AN XY: 133724

Gnomad AFR exome AF: 0.000829

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.000557

Gnomad NFE exome AF: 0.00377

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00325 AC: 4743 AN: 1461108 Hom.: 13 Cov.: 33 AF XY: 0.00317 AC XY: 2303 AN XY: 726820

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.000679

Gnomad4 NFE exome AF: 0.00403

Gnomad4 OTH exome AF: 0.00277

GnomAD4 genome AF: 0.00206 AC: 313 AN: 152278 Hom.: 0 Cov.: 31 AF XY: 0.00157 AC XY: 117 AN XY: 74462

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00379

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00269 Hom.: 1

Bravo AF: 0.00207

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000571 AC: 1

ESP6500EA AF: 0.00402 AC: 16

ExAC AF: 0.00202 AC: 240

EpiCase AF: 0.00349

EpiControl AF: 0.00284

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 21, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	TTN: BP4 -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

TTN-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 12, 2020

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

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2016

- -

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_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Uncertain	0.98
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
Vest4		0.13
MVP		0.42
MPC		0.11
ClinPred		0.0017	T
GERP RS		3.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200513156; hg19: chr2-179528759;