rs200021871

chr2-178658787-T-Achr2-178658787-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):c.37461A>T(p.Glu12487Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 147,606 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E12487E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (2 hom., cov: 19)
  • Exomes 𝑓: 0.023 (96 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.60

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 where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.001691848).
• BP6: Variant 2-178658787-T-A is Benign according to our data. Variant chr2-178658787-T-A is described in ClinVar as [Benign]. Clinvar id is 192213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178658787-T-A is described in Lovd as [Benign]. Variant chr2-178658787-T-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.37461A>T	p.Glu12487Asp	missense_variant	183/363	ENST00000589042.5
LOC124906100	XR_007087318.1	n.2185+14286T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.37461A>T	p.Glu12487Asp	missense_variant	183/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.502+61106T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 2899 AN: 147482 Hom.: 2 Cov.: 19

Gnomad AFR AF: 0.00414

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.0171

Gnomad EAS AF: 0.0730

Gnomad SAS AF: 0.0243

Gnomad FIN AF: 0.0394

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0220

Gnomad OTH AF: 0.0188

GnomAD3 exomes AF: 0.0268 AC: 6498 AN: 242278 Hom.: 4 AF XY: 0.0261 AC XY: 3445 AN XY: 131740

Gnomad AFR exome AF: 0.00416

Gnomad AMR exome AF: 0.0285

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.0725

Gnomad SAS exome AF: 0.0219

Gnomad FIN exome AF: 0.0421

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0263

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0228 AC: 33001 AN: 1447754 Hom.: 96 Cov.: 31 AF XY: 0.0229 AC XY: 16523 AN XY: 720288

Gnomad4 AFR exome AF: 0.00402

Gnomad4 AMR exome AF: 0.0283

Gnomad4 ASJ exome AF: 0.0140

Gnomad4 EAS exome AF: 0.0760

Gnomad4 SAS exome AF: 0.0227

Gnomad4 FIN exome AF: 0.0448

Gnomad4 NFE exome AF: 0.0205

Gnomad4 OTH exome AF: 0.0227

GnomAD4 genome AF: 0.0196 AC: 2900 AN: 147606 Hom.: 2 Cov.: 19 AF XY: 0.0203 AC XY: 1460 AN XY: 71862

Gnomad4 AFR AF: 0.00413

Gnomad4 AMR AF: 0.0197

Gnomad4 ASJ AF: 0.0171

Gnomad4 EAS AF: 0.0734

Gnomad4 SAS AF: 0.0243

Gnomad4 FIN AF: 0.0394

Gnomad4 NFE AF: 0.0220

Gnomad4 OTH AF: 0.0186

Alfa AF: 0.0198 Hom.: 2

ESP6500AA AF: 0.00514 AC: 9

ESP6500EA AF: 0.0151 AC: 60

ExAC AF: 0.0303 AC: 3648

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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	Jun 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 18, 2018	- -

not specified Benign:2

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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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 24, 2024

- -

Early-onset myopathy with fatal cardiomyopathy 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

- -

Tibial muscular dystrophy 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	-0.55	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	6.9
Dann	Benign	0.87
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.27	T;.
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.90	D;D;D;D;N;N
Vest4		0.099
MPC		0.13
ClinPred		0.0053	T
GERP RS		-1.0

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: rs200021871; hg19: chr2-179523514; COSMIC: COSV99045616; COSMIC: COSV99045616;