rs36051007

chr2-178681132-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.33287G>A(p.Arg11096His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 1,602,616 control chromosomes in the GnomAD database, including 68,020 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict 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. R11096C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.21 (4618 hom., cov: 32)
  • Exomes 𝑓: 0.29 (63402 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: -2.08

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]

LOC124906100 (HGNC:):

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=0.0017898977).
• BP6: Variant 2-178681132-C-T is Benign according to our data. Variant chr2-178681132-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178681132-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.33287G>A	p.Arg11096His	missense_variant	138/363	ENST00000589042.5
LOC124906100	XR_007087318.1	n.2186-32622C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.33287G>A	p.Arg11096His	missense_variant	138/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.503-53372C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32417 AN: 151770 Hom.: 4621 Cov.: 32

Gnomad AFR AF: 0.0539

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.0450

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.200

GnomAD3 exomes AF: 0.231 AC: 55369 AN: 239322 Hom.: 7894 AF XY: 0.238 AC XY: 30846 AN XY: 129712

Gnomad AFR exome AF: 0.0473

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.202

Gnomad EAS exome AF: 0.0377

Gnomad SAS exome AF: 0.208

Gnomad FIN exome AF: 0.380

Gnomad NFE exome AF: 0.303

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.286 AC: 414269 AN: 1450728 Hom.: 63402 Cov.: 33 AF XY: 0.284 AC XY: 204732 AN XY: 721132

Gnomad4 AFR exome AF: 0.0421

Gnomad4 AMR exome AF: 0.111

Gnomad4 ASJ exome AF: 0.205

Gnomad4 EAS exome AF: 0.0423

Gnomad4 SAS exome AF: 0.213

Gnomad4 FIN exome AF: 0.375

Gnomad4 NFE exome AF: 0.313

Gnomad4 OTH exome AF: 0.257

GnomAD4 genome AF: 0.213 AC: 32404 AN: 151888 Hom.: 4618 Cov.: 32 AF XY: 0.212 AC XY: 15768 AN XY: 74254

Gnomad4 AFR AF: 0.0537

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.205

Gnomad4 EAS AF: 0.0449

Gnomad4 SAS AF: 0.214

Gnomad4 FIN AF: 0.384

Gnomad4 NFE AF: 0.312

Gnomad4 OTH AF: 0.199

Alfa AF: 0.282 Hom.: 10138

Bravo AF: 0.184

TwinsUK AF: 0.311 AC: 1155

ALSPAC AF: 0.326 AC: 1257

ESP6500AA AF: 0.0528 AC: 190

ESP6500EA AF: 0.303 AC: 2467

ExAC AF: 0.233 AC: 28183

Asia WGS AF: 0.120 AC: 417 AN: 3478

EpiCase AF: 0.295

EpiControl AF: 0.283

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

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	Aug 16, 2020	- -
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 23, 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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Clinical Genetics, Academic 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	-	- -

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	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. -
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 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. -
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 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

Invitae

Feb 01, 2024

- -

Dilated cardiomyopathy 1G Benign:1

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 02, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 15, 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	0.056
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	5.8
Dann	Benign	0.85
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.42	T;T;.;T
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.29	N;.;.;.
REVEL	Benign	0.062
Sift	Benign	0.42	T;.;.;.
Polyphen		0.0	.;.;B;B
Vest4		0.034
MPC		0.10
ClinPred		0.0044	T
GERP RS		-2.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs36051007; hg19: chr2-179545859; COSMIC: COSV60215351;