rs369544339

Positions:

• chr2-178729493-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4_Strong BP6

The NM_001267550.2(TTN):​c.18663A>C​(p.Glu6221Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,613,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 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. E6221G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 0.814

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 Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.055708796).
• BP6: Variant 2-178729493-T-G is Benign according to our data. Variant chr2-178729493-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46642.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}. Variant chr2-178729493-T-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.18663A>C	p.Glu6221Asp	missense_variant	64/363	ENST00000589042.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.18663A>C	p.Glu6221Asp	missense_variant	64/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.503-5011T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000926 AC: 23 AN: 248470 Hom.: 0 AF XY: 0.0000965 AC XY: 13 AN XY: 134784

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000712

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000112 AC: 164 AN: 1461374 Hom.: 0 Cov.: 33 AF XY: 0.000114 AC XY: 83 AN XY: 726970

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000936

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74456

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000106

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000243 AC: 2

ExAC AF: 0.0000993 AC: 12

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 28, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2019	This variant is associated with the following publications: (PMID: 24503780) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 20, 2015	The p.Glu4977Asp variant in TTN has been previously identified by our laboratory in 1 Caucasian child with DCM and 1 Caucasian adult with ARVC. This variant has also been identified in 11/67530 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs369544339). Computatio nal prediction tools and conservation analysis suggest the p.Glu4977Asp variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Glu4977As p variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 27, 2019	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Benign	0.81
Eigen	Benign	0.10
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.71	T;T;.;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.056	T;T;T;T
MetaSVM	Benign	-0.69	T
MutationTaster	Benign	1.0	D;D;D;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.9	N;.;.;.
REVEL	Benign	0.15
Sift	Benign	0.34	T;.;.;.
Polyphen		0.92	.;.;P;P
Vest4		0.33
MutPred		0.39		.;.;Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP		0.25
MPC		0.20
ClinPred		0.090	T
GERP RS		2.2

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: rs369544339; hg19: chr2-179594220; COSMIC: COSV60390876; COSMIC: COSV60390876;