rs2244492

Variant names:

• chr2-178689578-C-T
• rs2244492
• NM_001267550.2:c.31864G>A

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.31864G>A​(p.Gly10622Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,603,082 control chromosomes in the GnomAD database, including 122,135 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15809 hom., cov: 32)
  • Exomes 𝑓: 0.38 (106326 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 1.72

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]

LOC124907912 (HGNC:):

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=2.2068143E-5).
• BP6: Variant 2-178689578-C-T is Benign according to our data. Variant chr2-178689578-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178689578-C-T is described in Lovd as [Benign]. Variant chr2-178689578-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.31864G>A	p.Gly10622Arg	missense_variant	Exon 123 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.31864G>A	p.Gly10622Arg	missense_variant	Exon 123 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66544 AN: 151906 Hom.: 15767 Cov.: 32

Gnomad AFR AF: 0.601

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.505

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.378

GnomAD3 exomes AF: 0.380 AC: 89586 AN: 235902 Hom.: 17887 AF XY: 0.377 AC XY: 48110 AN XY: 127592

Gnomad AFR exome AF: 0.607

Gnomad AMR exome AF: 0.362

Gnomad ASJ exome AF: 0.273

Gnomad EAS exome AF: 0.168

Gnomad SAS exome AF: 0.453

Gnomad FIN exome AF: 0.498

Gnomad NFE exome AF: 0.356

Gnomad OTH exome AF: 0.349

GnomAD4 exome AF: 0.377 AC: 546651 AN: 1451056 Hom.: 106326 Cov.: 34 AF XY: 0.377 AC XY: 271718 AN XY: 721110

Gnomad4 AFR exome AF: 0.618

Gnomad4 AMR exome AF: 0.366

Gnomad4 ASJ exome AF: 0.275

Gnomad4 EAS exome AF: 0.149

Gnomad4 SAS exome AF: 0.450

Gnomad4 FIN exome AF: 0.497

Gnomad4 NFE exome AF: 0.370

Gnomad4 OTH exome AF: 0.374

GnomAD4 genome AF: 0.438 AC: 66650 AN: 152026 Hom.: 15809 Cov.: 32 AF XY: 0.441 AC XY: 32745 AN XY: 74286

Gnomad4 AFR AF: 0.602

Gnomad4 AMR AF: 0.391

Gnomad4 ASJ AF: 0.277

Gnomad4 EAS AF: 0.170

Gnomad4 SAS AF: 0.458

Gnomad4 FIN AF: 0.505

Gnomad4 NFE AF: 0.370

Gnomad4 OTH AF: 0.379

Alfa AF: 0.366 Hom.: 24003

Bravo AF: 0.429

TwinsUK AF: 0.369 AC: 1369

ALSPAC AF: 0.381 AC: 1469

ESP6500AA AF: 0.595 AC: 2207

ESP6500EA AF: 0.360 AC: 2955

ExAC AF: 0.378 AC: 45629

Asia WGS AF: 0.337 AC: 1169 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:23

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:10

Aug 08, 2020

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 26, 2012

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: 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

- -

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 12, 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 12, 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

- -

Nov 28, 2018

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 12, 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 12, 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 12, 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. -

Cardiovascular phenotype Benign:1

Jan 09, 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	0.063
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.0072	.;.;.;.;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.21	T;T;.;T;T
MetaRNN	Benign	0.000022	T;T;T;T;T
MetaSVM	Benign	-0.95	T
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.8	N;.;.;.;N
REVEL	Benign	0.094
Sift	Benign	0.80	T;.;.;.;T
Vest4		0.072
MutPred		0.36		Gain of MoRF binding (P = 0.0075);.;.;.;.;
ClinPred		0.012	T
GERP RS		5.3

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: rs2244492; hg19: chr2-179554305; COSMIC: COSV59946355;