rs771284532

chr2-178599442-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4 BP6

The NM_001267550.2(TTN):c.56351G>A(p.Arg18784His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000497 in 1,528,552 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: 3.26

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 -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.28282443).
• BP6: Variant 2-178599442-C-T is Benign according to our data. Variant chr2-178599442-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 467289.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.56351G>A	p.Arg18784His	missense_variant	290/363	ENST00000589042.5
TTN-AS1	NR_038272.1	n.3569-152C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.56351G>A	p.Arg18784His	missense_variant	290/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.502+1761C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151990 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000762 AC: 14 AN: 183726 Hom.: 0 AF XY: 0.0000920 AC XY: 9 AN XY: 97824

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000626

Gnomad FIN exome AF: 0.0000558

Gnomad NFE exome AF: 0.0000898

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000501 AC: 69 AN: 1376562 Hom.: 1 Cov.: 32 AF XY: 0.0000517 AC XY: 35 AN XY: 676474

Gnomad4 AFR exome AF: 0.0000329

Gnomad4 AMR exome AF: 0.000127

Gnomad4 ASJ exome AF: 0.0000472

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000724

Gnomad4 FIN exome AF: 0.0000198

Gnomad4 NFE exome AF: 0.0000494

Gnomad4 OTH exome AF: 0.0000529

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151990 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74206

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000436 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000831 AC: 10

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:6

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 26, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 15, 2017

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 13, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Feb 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	23
Dann	Benign	0.93
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;.;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.7	D;D;.;.;D;D;.
REVEL	Benign	0.29
Sift	Uncertain	0.0070	D;D;.;.;D;D;.
Polyphen		1.0	.;.;.;D;.;.;D
Vest4		0.42
MutPred		0.44		.;.;.;Loss of methylation at R17143 (P = 0.0216);.;.;Loss of methylation at R17143 (P = 0.0216);
MVP		0.25
MPC		0.44
ClinPred		0.25	T
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs771284532; hg19: chr2-179464169; COSMIC: COSV59886799; COSMIC: COSV59886799;