chr2-178747656-C-T

Position:

• chr2-178747656-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133379.5(TTN):​c.14744G>A​(p.Arg4915His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0484 in 1,613,178 control chromosomes in the GnomAD database, including 2,243 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (146 hom., cov: 32)
  • Exomes 𝑓: 0.050 (2097 hom.)
• Consequence: TTN NM_133379.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.17

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017179251).
• BP6: Variant 2-178747656-C-T is Benign according to our data. Variant chr2-178747656-C-T is described in ClinVar as [Benign]. Clinvar id is 47775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178747656-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_133379.5	c.14744G>A	p.Arg4915His	missense_variant	46/46	ENST00000360870.10	NP_596870.2
TTN	NM_001267550.2	c.11311+5468G>A		intron_variant		ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000360870.10	c.14744G>A	p.Arg4915His	missense_variant	46/46	5	NM_133379.5	ENSP00000354117.4
TTN	ENST00000589042.5	c.11311+5468G>A		intron_variant		5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0344 AC: 5229 AN: 151982 Hom.: 146 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0297

Gnomad ASJ AF: 0.0257

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0388

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0549

Gnomad OTH AF: 0.0417

GnomAD3 exomes AF: 0.0350 AC: 8746 AN: 250138 Hom.: 222 AF XY: 0.0351 AC XY: 4750 AN XY: 135180

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.0209

Gnomad ASJ exome AF: 0.0253

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00206

Gnomad FIN exome AF: 0.0374

Gnomad NFE exome AF: 0.0577

Gnomad OTH exome AF: 0.0366

GnomAD4 exome AF: 0.0499 AC: 72908 AN: 1461078 Hom.: 2097 Cov.: 35 AF XY: 0.0487 AC XY: 35378 AN XY: 726850

Gnomad4 AFR exome AF: 0.00888

Gnomad4 AMR exome AF: 0.0215

Gnomad4 ASJ exome AF: 0.0264

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00256

Gnomad4 FIN exome AF: 0.0388

Gnomad4 NFE exome AF: 0.0595

Gnomad4 OTH exome AF: 0.0395

GnomAD4 genome AF: 0.0344 AC: 5229 AN: 152100 Hom.: 146 Cov.: 32 AF XY: 0.0323 AC XY: 2401 AN XY: 74370

Gnomad4 AFR AF: 0.0105

Gnomad4 AMR AF: 0.0297

Gnomad4 ASJ AF: 0.0257

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0388

Gnomad4 NFE AF: 0.0549

Gnomad4 OTH AF: 0.0412

Alfa AF: 0.0472 Hom.: 323

Bravo AF: 0.0330

TwinsUK AF: 0.0628 AC: 233

ALSPAC AF: 0.0669 AC: 258

ESP6500AA AF: 0.0116 AC: 51

ESP6500EA AF: 0.0582 AC: 500

ExAC AF: 0.0358 AC: 4353

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0533

EpiControl AF: 0.0554

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 16, 2011	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2013	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. -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.9
DANN	Benign	0.63
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00051	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.070
Sift	Benign	0.42	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.024
ClinPred		0.016	T
GERP RS		1.8

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: rs72648907; hg19: chr2-179612383;