rs2742347

chr2-178735921-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.14525G>A(p.Arg4842Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0669 in 1,613,726 control chromosomes in the GnomAD database, including 6,116 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/15 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. R4842R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1400 hom., cov: 32)
  • Exomes 𝑓: 0.062 (4716 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 0.507

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.0045004487).
• BP6: Variant 2-178735921-C-T is Benign according to our data. Variant chr2-178735921-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178735921-C-T is described in Lovd as [Benign]. Variant chr2-178735921-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.14525G>A	p.Arg4842Lys	missense_variant	50/363	ENST00000589042.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.14525G>A	p.Arg4842Lys	missense_variant	50/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.773+49C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16910 AN: 152018 Hom.: 1383 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.0712

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.0483

Gnomad FIN AF: 0.0511

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0481

Gnomad OTH AF: 0.100

GnomAD3 exomes AF: 0.0995 AC: 24778 AN: 248924 Hom.: 2213 AF XY: 0.0877 AC XY: 11841 AN XY: 135018

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.252

Gnomad ASJ exome AF: 0.0717

Gnomad EAS exome AF: 0.209

Gnomad SAS exome AF: 0.0422

Gnomad FIN exome AF: 0.0524

Gnomad NFE exome AF: 0.0475

Gnomad OTH exome AF: 0.0813

GnomAD4 exome AF: 0.0623 AC: 91014 AN: 1461590 Hom.: 4716 Cov.: 36 AF XY: 0.0603 AC XY: 43841 AN XY: 727086

Gnomad4 AFR exome AF: 0.220

Gnomad4 AMR exome AF: 0.241

Gnomad4 ASJ exome AF: 0.0720

Gnomad4 EAS exome AF: 0.190

Gnomad4 SAS exome AF: 0.0424

Gnomad4 FIN exome AF: 0.0547

Gnomad4 NFE exome AF: 0.0471

Gnomad4 OTH exome AF: 0.0720

GnomAD4 genome AF: 0.112 AC: 16986 AN: 152136 Hom.: 1400 Cov.: 32 AF XY: 0.112 AC XY: 8332 AN XY: 74362

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.0712

Gnomad4 EAS AF: 0.189

Gnomad4 SAS AF: 0.0485

Gnomad4 FIN AF: 0.0511

Gnomad4 NFE AF: 0.0481

Gnomad4 OTH AF: 0.0985

Alfa AF: 0.0632 Hom.: 940

Bravo AF: 0.130

TwinsUK AF: 0.0485 AC: 180

ALSPAC AF: 0.0503 AC: 194

ESP6500AA AF: 0.203 AC: 789

ESP6500EA AF: 0.0479 AC: 397

ExAC AF: 0.0958 AC: 11573

Asia WGS AF: 0.105 AC: 364 AN: 3476

EpiCase AF: 0.0449

EpiControl AF: 0.0475

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	Eurofins Ntd Llc (ga)	May 29, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 24, 2012	Classified as benign based on high population frequency -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 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	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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	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	- -

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	- -

Tibial muscular dystrophy 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 17, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	6.7
Dann	Benign	0.62
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.26	T;T;.;T
MetaRNN	Benign	0.0045	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.11	N;.;.;.
REVEL	Benign	0.049
Sift	Benign	0.97	T;.;.;.
Vest4		0.017
ClinPred		0.0030	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: rs2742347; hg19: chr2-179600648; COSMIC: COSV59946464; COSMIC: COSV59946464;