rs2042995

Variant names:

• chr2-178693639-T-C
• rs2042995
• NM_001267550.2:c.31564A>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.31564A>G​(p.Ile10522Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 1,596,826 control chromosomes in the GnomAD database, including 69,862 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 0.36 (11636 hom., cov: 32)
  • Exomes 𝑓: 0.27 (58226 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 1.46

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=3.0493736E-4).
• BP6: Variant 2-178693639-T-C is Benign according to our data. Variant chr2-178693639-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 46852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178693639-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.31564A>G	p.Ile10522Val	missense_variant	Exon 119 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.31564A>G	p.Ile10522Val	missense_variant	Exon 119 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54609 AN: 151908 Hom.: 11586 Cov.: 32

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.557

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.572

Gnomad SAS AF: 0.484

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.328

GnomAD3 exomes AF: 0.337 AC: 82484 AN: 245066 Hom.: 16145 AF XY: 0.332 AC XY: 44145 AN XY: 132844

Gnomad AFR exome AF: 0.558

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.267

Gnomad EAS exome AF: 0.574

Gnomad SAS exome AF: 0.480

Gnomad FIN exome AF: 0.252

Gnomad NFE exome AF: 0.227

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.265 AC: 382959 AN: 1444798 Hom.: 58226 Cov.: 31 AF XY: 0.269 AC XY: 192594 AN XY: 716090

Gnomad4 AFR exome AF: 0.567

Gnomad4 AMR exome AF: 0.429

Gnomad4 ASJ exome AF: 0.266

Gnomad4 EAS exome AF: 0.559

Gnomad4 SAS exome AF: 0.469

Gnomad4 FIN exome AF: 0.252

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.295

GnomAD4 genome AF: 0.360 AC: 54721 AN: 152028 Hom.: 11636 Cov.: 32 AF XY: 0.367 AC XY: 27299 AN XY: 74326

Gnomad4 AFR AF: 0.553

Gnomad4 AMR AF: 0.391

Gnomad4 ASJ AF: 0.267

Gnomad4 EAS AF: 0.572

Gnomad4 SAS AF: 0.482

Gnomad4 FIN AF: 0.260

Gnomad4 NFE AF: 0.229

Gnomad4 OTH AF: 0.335

Alfa AF: 0.263 Hom.: 14861

Bravo AF: 0.377

TwinsUK AF: 0.218 AC: 809

ALSPAC AF: 0.222 AC: 854

ESP6500AA AF: 0.559 AC: 2003

ESP6500EA AF: 0.229 AC: 1858

ExAC AF: 0.338 AC: 40747

Asia WGS AF: 0.543 AC: 1889 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Sep 27, 2011

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

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 18, 2020

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 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. -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

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. -

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early-onset myopathy with fatal cardiomyopathy Benign:2

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. -

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 19, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Tibial muscular dystrophy Benign:2

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. -

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myopathy, myofibrillar, 9, with early respiratory failure Benign:2

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. -

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: 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 16, 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	0.059
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.71
DEOGEN2	Benign	0.0062	.;.;.;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.0020
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.29	T;T;.;T;T
MetaRNN	Benign	0.00030	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.28	N;.;.;.;N
REVEL	Benign	0.077
Sift	Benign	1.0	T;.;.;.;T
Vest4		0.025
ClinPred		0.0060	T
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2042995; hg19: chr2-179558366; COSMIC: COSV60092594;