rs72647843

Positions:

• chr2-178800436-C-T

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.542G>A​(p.Ser181Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,614,158 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (87 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (64 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 2.83

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TTN. . Gene score misZ -1.1021 (greater than the threshold 3.09). Trascript score misZ 6.9794 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, tibial muscular dystrophy, early-onset myopathy with fatal cardiomyopathy, autosomal recessive centronuclear myopathy, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 9, TTN-related myopathy, dilated cardiomyopathy 1G, arrhythmogenic right ventricular cardiomyopathy, myopathy, myofibrillar, 9, with early respiratory failure, familial isolated dilated cardiomyopathy, childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome, autosomal recessive limb-girdle muscular dystrophy type 2J.
• BP4: Computational evidence support a benign effect (MetaRNN=0.004034966).
• BP6: Variant 2-178800436-C-T is Benign according to our data. Variant chr2-178800436-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 47178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178800436-C-T is described in Lovd as [Benign]. Variant chr2-178800436-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.542G>A	p.Ser181Asn	missense_variant	4/363	ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.542G>A	p.Ser181Asn	missense_variant	4/46	ENST00000360870.10	NP_596870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.542G>A	p.Ser181Asn	missense_variant	4/363	5	NM_001267550.2	ENSP00000467141.1
TTN	ENST00000360870.10	c.542G>A	p.Ser181Asn	missense_variant	4/46	5	NM_133379.5	ENSP00000354117.4

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2499 AN: 152180 Hom.: 87 Cov.: 32

Gnomad AFR AF: 0.0567

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00621

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00456 AC: 1147 AN: 251376 Hom.: 37 AF XY: 0.00343 AC XY: 466 AN XY: 135848

Gnomad AFR exome AF: 0.0593

Gnomad AMR exome AF: 0.00341

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000431

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00182 AC: 2657 AN: 1461860 Hom.: 64 Cov.: 31 AF XY: 0.00159 AC XY: 1156 AN XY: 727238

Gnomad4 AFR exome AF: 0.0590

Gnomad4 AMR exome AF: 0.00360

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000226

Gnomad4 OTH exome AF: 0.00401

GnomAD4 genome AF: 0.0164 AC: 2501 AN: 152298 Hom.: 87 Cov.: 32 AF XY: 0.0158 AC XY: 1177 AN XY: 74468

Gnomad4 AFR AF: 0.0566

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00333 Hom.: 19

Bravo AF: 0.0188

ESP6500AA AF: 0.0626 AC: 276

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00553 AC: 671

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000475

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:23

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 06, 2019	Variant summary: TTN c.542G>A (p.Ser181Asn) results in a conservative amino acid change located in the Z-disk region of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0046 in 251376 control chromosomes, predominantly at a frequency of 0.059 within the African or African-American subpopulation in the gnomAD database, including 37 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 94- fold the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.542G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating an impact on protein function have been reported in the literature. Co-occurrence with another pathogenic variant has been reported (TTR c.424G>A, p.Val142Ile; internal sample), providing supporting evidence for a benign role. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2014	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
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	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 24, 2012	6.2% (232/3738) of Afr Amer chrom in ESP -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Aug 16, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2J 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 12, 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. -

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 12, 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	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 12, 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Feb 05, 2016

- -

Dilated cardiomyopathy 1G Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

Jul 18, 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	Benign	0.15
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Benign	0.92
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;D;D;.;D;D;D;D
MetaRNN	Benign	0.0040	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.6	N;N;.;.;N;N;.;N
REVEL	Benign	0.16
Sift	Benign	0.080	T;T;.;.;T;T;.;T
Sift4G	Benign	0.11	.;.;.;.;.;.;.;T
Polyphen		0.0020, 0.094	.;.;.;B;.;.;B;B
Vest4		0.38
MVP		0.21
MPC		0.079
ClinPred		0.010	T
GERP RS		6.0

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: rs72647843; hg19: chr2-179665163;