rs35813871

chr2-178785681-G-A

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.2432C>T(p.Thr811Ile) variant causes a missense change. The variant allele was found at a frequency of 0.21 in 1,614,008 control chromosomes in the GnomAD database, including 39,606 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2675 hom., cov: 32)
  • Exomes 𝑓: 0.21 (36931 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 5.94

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=0.0015586615).
• BP6: Variant 2-178785681-G-A is Benign according to our data. Variant chr2-178785681-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 46805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178785681-G-A is described in Lovd as [Benign]. Variant chr2-178785681-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.2432C>T	p.Thr811Ile	missense_variant	15/363	ENST00000589042.5
TTN	NM_133379.5	c.2432C>T	p.Thr811Ile	missense_variant	15/46	ENST00000360870.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.2432C>T	p.Thr811Ile	missense_variant	15/363	5	NM_001267550.2	P1
TTN	ENST00000360870.10	c.2432C>T	p.Thr811Ile	missense_variant	15/46	5	NM_133379.5

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26159 AN: 152086 Hom.: 2676 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0738

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.220

GnomAD3 exomes AF: 0.170 AC: 42633 AN: 251288 Hom.: 4601 AF XY: 0.173 AC XY: 23550 AN XY: 135806

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.329

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0791

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.209

GnomAD4 exome AF: 0.214 AC: 312429 AN: 1461804 Hom.: 36931 Cov.: 36 AF XY: 0.211 AC XY: 153616 AN XY: 727208

Gnomad4 AFR exome AF: 0.0998

Gnomad4 AMR exome AF: 0.124

Gnomad4 ASJ exome AF: 0.334

Gnomad4 EAS exome AF: 0.000554

Gnomad4 SAS exome AF: 0.0832

Gnomad4 FIN exome AF: 0.137

Gnomad4 NFE exome AF: 0.239

Gnomad4 OTH exome AF: 0.210

GnomAD4 genome AF: 0.172 AC: 26151 AN: 152204 Hom.: 2675 Cov.: 32 AF XY: 0.165 AC XY: 12292 AN XY: 74408

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.170

Gnomad4 ASJ AF: 0.325

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0730

Gnomad4 FIN AF: 0.124

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.218

Alfa AF: 0.214 Hom.: 2354

Bravo AF: 0.174

TwinsUK AF: 0.247 AC: 915

ALSPAC AF: 0.246 AC: 947

ESP6500AA AF: 0.102 AC: 450

ESP6500EA AF: 0.235 AC: 2017

ExAC AF: 0.169 AC: 20517

Asia WGS AF: 0.0460 AC: 163 AN: 3476

EpiCase AF: 0.253

EpiControl AF: 0.257

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 08, 2020	- -
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	Sep 16, 2011	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	Aug 15, 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. -

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 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. -

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	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	- -

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. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2019

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	-0.33	T
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	23
Dann	Benign	0.94
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D;D;.;D;D;D;D
MetaRNN	Benign	0.0016	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.73	P;P;P;P;P;P;P
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.2	D;D;.;.;D;D;.;D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D;.;.;D;D;.;D
Polyphen		1.0, 1.0	.;.;.;D;.;.;D;D
Vest4		0.20
MPC		0.29
ClinPred		0.061	T
GERP RS		5.5

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: rs35813871; hg19: chr2-179650408; COSMIC: COSV60066380; COSMIC: COSV60066380;