rs2288563

Variant names:

• chr2-178634803-T-C
• rs2288563
• NM_001267550.2:c.42071A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-178634803-T-C
• chr2-178634803-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.42071A>G​(p.His14024Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0236 in 1,612,854 control chromosomes in the GnomAD database, including 661 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (69 hom., cov: 32)
  • Exomes 𝑓: 0.024 (592 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 5.87

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016076267).
• BP6: Variant 2-178634803-T-C is Benign according to our data. Variant chr2-178634803-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 46952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178634803-T-C is described in Lovd as [Benign]. Variant chr2-178634803-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.42071A>G	p.His14024Arg	missense_variant	Exon 229 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.42071A>G	p.His14024Arg	missense_variant	Exon 229 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3272 AN: 152124 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.00461

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.0966

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.0452

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0216

GnomAD3 exomes AF: 0.0290 AC: 7181 AN: 247948 Hom.: 181 AF XY: 0.0271 AC XY: 3650 AN XY: 134514

Gnomad AFR exome AF: 0.00505

Gnomad AMR exome AF: 0.0335

Gnomad ASJ exome AF: 0.0142

Gnomad EAS exome AF: 0.103

Gnomad SAS exome AF: 0.00638

Gnomad FIN exome AF: 0.0475

Gnomad NFE exome AF: 0.0231

Gnomad OTH exome AF: 0.0271

GnomAD4 exome AF: 0.0239 AC: 34837 AN: 1460612 Hom.: 592 Cov.: 32 AF XY: 0.0233 AC XY: 16952 AN XY: 726568

Gnomad4 AFR exome AF: 0.00410

Gnomad4 AMR exome AF: 0.0317

Gnomad4 ASJ exome AF: 0.0143

Gnomad4 EAS exome AF: 0.0957

Gnomad4 SAS exome AF: 0.00695

Gnomad4 FIN exome AF: 0.0490

Gnomad4 NFE exome AF: 0.0220

Gnomad4 OTH exome AF: 0.0235

GnomAD4 genome AF: 0.0215 AC: 3269 AN: 152242 Hom.: 69 Cov.: 32 AF XY: 0.0220 AC XY: 1636 AN XY: 74424

Gnomad4 AFR AF: 0.00459

Gnomad4 AMR AF: 0.0232

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.0968

Gnomad4 SAS AF: 0.00745

Gnomad4 FIN AF: 0.0452

Gnomad4 NFE AF: 0.0231

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0218 Hom.: 78

Bravo AF: 0.0199

TwinsUK AF: 0.0251 AC: 93

ALSPAC AF: 0.0228 AC: 88

ESP6500AA AF: 0.00547 AC: 20

ESP6500EA AF: 0.0205 AC: 168

ExAC AF: 0.0291 AC: 3512

Asia WGS AF: 0.0360 AC: 126 AN: 3478

EpiCase AF: 0.0199

EpiControl AF: 0.0215

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Apr 24, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 29, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 11, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 16, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tibial muscular dystrophy Benign:2

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1G Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 04, 2013

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.19
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.94
Eigen	Benign	0.036
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T;T;T;.;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.93	.;.;.;L;.;.;L
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.7	D;D;.;.;D;D;.
REVEL	Benign	0.13
Sift	Benign	0.53	T;T;.;.;T;T;.
Vest4		0.28
MPC		0.11
ClinPred		0.015	T
GERP RS		5.0

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: rs2288563; hg19: chr2-179499530; COSMIC: COSV99045732; COSMIC: COSV99045732;