rs16866538

chr2-178795185-G-Achr2-178795185-G-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.982C>T(p.Arg328Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0835 in 1,613,984 control chromosomes in the GnomAD database, including 13,306 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R328H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (1792 hom., cov: 32)
  • Exomes 𝑓: 0.081 (11514 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 5.45

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=2.1404028E-4).
• BP6: Variant 2-178795185-G-A is Benign according to our data. Variant chr2-178795185-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 47703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178795185-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.982C>T	p.Arg328Cys	missense_variant	7/363	ENST00000589042.5
TTN	NM_133379.5	c.982C>T	p.Arg328Cys	missense_variant	7/46	ENST00000360870.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.982C>T	p.Arg328Cys	missense_variant	7/363	5	NM_001267550.2	P1
TTN	ENST00000360870.10	c.982C>T	p.Arg328Cys	missense_variant	7/46	5	NM_133379.5

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16910 AN: 152028 Hom.: 1794 Cov.: 32

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.0928

Gnomad ASJ AF: 0.0617

Gnomad EAS AF: 0.581

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.0535

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0525

Gnomad OTH AF: 0.0927

GnomAD3 exomes AF: 0.124 AC: 31037 AN: 250968 Hom.: 4537 AF XY: 0.122 AC XY: 16554 AN XY: 135624

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.0662

Gnomad EAS exome AF: 0.597

Gnomad SAS exome AF: 0.188

Gnomad FIN exome AF: 0.0489

Gnomad NFE exome AF: 0.0513

Gnomad OTH exome AF: 0.0844

GnomAD4 exome AF: 0.0806 AC: 117804 AN: 1461838 Hom.: 11514 Cov.: 33 AF XY: 0.0829 AC XY: 60293 AN XY: 727230

Gnomad4 AFR exome AF: 0.171

Gnomad4 AMR exome AF: 0.0997

Gnomad4 ASJ exome AF: 0.0647

Gnomad4 EAS exome AF: 0.596

Gnomad4 SAS exome AF: 0.184

Gnomad4 FIN exome AF: 0.0462

Gnomad4 NFE exome AF: 0.0518

Gnomad4 OTH exome AF: 0.0990

GnomAD4 genome AF: 0.111 AC: 16923 AN: 152146 Hom.: 1792 Cov.: 32 AF XY: 0.115 AC XY: 8559 AN XY: 74364

Gnomad4 AFR AF: 0.167

Gnomad4 AMR AF: 0.0929

Gnomad4 ASJ AF: 0.0617

Gnomad4 EAS AF: 0.580

Gnomad4 SAS AF: 0.190

Gnomad4 FIN AF: 0.0535

Gnomad4 NFE AF: 0.0525

Gnomad4 OTH AF: 0.0965

Alfa AF: 0.0731 Hom.: 2308

Bravo AF: 0.119

TwinsUK AF: 0.0464 AC: 172

ALSPAC AF: 0.0514 AC: 198

ESP6500AA AF: 0.156 AC: 689

ESP6500EA AF: 0.0531 AC: 457

ExAC AF: 0.124 AC: 15044

Asia WGS AF: 0.362 AC: 1259 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 03, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 24, 2012	Arg328Cys in exon 7 of TTN: This variant is not expected to have clinical signif icance because it has been identified in 15.5% (578/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS/rs16866538). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 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, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2020	- -

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

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Early-onset myopathy with fatal cardiomyopathy 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. -

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

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. -
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

Feb 01, 2024

- -

Dilated cardiomyopathy 1G Benign:1

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 13, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2013

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	0.050
Cadd	Uncertain	23
Dann	Benign	0.68
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.077
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;.;D;D;D;D
MetaRNN	Benign	0.00021	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	0.00051	P;P;P;P;P;P;P
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.6	D;D;.;.;D;D;.;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0070	D;D;.;.;D;D;.;D
Polyphen		0.14, 0.77	.;.;.;B;.;.;B;P
Vest4		0.18
MPC		0.12
ClinPred		0.034	T
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs16866538; hg19: chr2-179659912; COSMIC: COSV60072022; COSMIC: COSV60072022;