rs72647851

Positions:

• chr2-178793448-C-T

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.1492G>A​(p.Val498Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0224 in 1,614,106 control chromosomes in the GnomAD database, including 481 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V498V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (25 hom., cov: 33)
  • Exomes 𝑓: 0.023 (456 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 1.45

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]

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=0.0036358535).
• BP6: Variant 2-178793448-C-T is Benign according to our data. Variant chr2-178793448-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178793448-C-T is described in Lovd as [Benign]. Variant chr2-178793448-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0164 (2500/152254) while in subpopulation NFE AF= 0.0232 (1580/68008). AF 95% confidence interval is 0.0223. There are 25 homozygotes in gnomad4. There are 1256 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 25 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.1492G>A	p.Val498Ile	missense_variant	9/363	ENST00000589042.5
TTN	NM_133379.5	c.1492G>A	p.Val498Ile	missense_variant	9/46	ENST00000360870.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.1492G>A	p.Val498Ile	missense_variant	9/363	5	NM_001267550.2	P1
TTN	ENST00000360870.10	c.1492G>A	p.Val498Ile	missense_variant	9/46	5	NM_133379.5

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2502 AN: 152136 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.00524

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.0313

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0232

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.0160 AC: 4034 AN: 251372 Hom.: 48 AF XY: 0.0164 AC XY: 2229 AN XY: 135860

Gnomad AFR exome AF: 0.00511

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00637

Gnomad FIN exome AF: 0.0273

Gnomad NFE exome AF: 0.0223

Gnomad OTH exome AF: 0.0223

GnomAD4 exome AF: 0.0230 AC: 33591 AN: 1461852 Hom.: 456 Cov.: 31 AF XY: 0.0224 AC XY: 16299 AN XY: 727232

Gnomad4 AFR exome AF: 0.00376

Gnomad4 AMR exome AF: 0.0140

Gnomad4 ASJ exome AF: 0.00482

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00646

Gnomad4 FIN exome AF: 0.0256

Gnomad4 NFE exome AF: 0.0265

Gnomad4 OTH exome AF: 0.0204

GnomAD4 genome AF: 0.0164 AC: 2500 AN: 152254 Hom.: 25 Cov.: 33 AF XY: 0.0169 AC XY: 1256 AN XY: 74452

Gnomad4 AFR AF: 0.00520

Gnomad4 AMR AF: 0.0173

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00745

Gnomad4 FIN AF: 0.0313

Gnomad4 NFE AF: 0.0232

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0215 Hom.: 51

Bravo AF: 0.0158

TwinsUK AF: 0.0321 AC: 119

ALSPAC AF: 0.0265 AC: 102

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.0233 AC: 200

ExAC AF: 0.0148 AC: 1801

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0243

EpiControl AF: 0.0230

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:26

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:11

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 18, 2012	Val498Ile in exon 9 of TTN: This variant is not expected to have clinical signif icance because it has been identified in 2.1% (150/7020) of European American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS/rs72647851). Val498Ile in exon 9 of TTN (rs72647851; allele frequency = 2.1%, 150/7020) ** -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 27, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2012	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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 11, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 31, 2019	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Early-onset myopathy with fatal cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Myopathy, myofibrillar, 9, with early respiratory failure Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Tibial muscular dystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Dilated cardiomyopathy 1G Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2012

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hypertrophic cardiomyopathy 2 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Institute of Human Genetics, University of Wuerzburg

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	19
DANN	Benign	0.95
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.017
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.68	T;T;T;.;T;T;T;T;T
MetaRNN	Benign	0.0036	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.84	D;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.52	N;N;.;.;N;N;.;N;N
REVEL	Benign	0.058
Sift	Benign	0.19	T;T;.;.;T;T;.;T;T
Polyphen		0.0, 0.0010	.;.;.;B;.;.;B;B;.
Vest4		0.090
MPC		0.069
ClinPred		0.0049	T
GERP RS		4.7

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: rs72647851; hg19: chr2-179658175;