rs56142888

chr2-178773134-C-Gchr2-178773134-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.7830G>C(p.Met2610Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0524 in 1,613,764 control chromosomes in the GnomAD database, including 3,776 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (364 hom., cov: 32)
  • Exomes 𝑓: 0.053 (3412 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 0.689

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.0010922849).
• BP6: Variant 2-178773134-C-G is Benign according to our data. Variant chr2-178773134-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 47451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178773134-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.7830G>C	p.Met2610Ile	missense_variant	33/363	ENST00000589042.5
TTN	NM_133379.5	c.7830G>C	p.Met2610Ile	missense_variant	33/46	ENST00000360870.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.7830G>C	p.Met2610Ile	missense_variant	33/363	5	NM_001267550.2	P1
TTN	ENST00000360870.10	c.7830G>C	p.Met2610Ile	missense_variant	33/46	5	NM_133379.5
TTN-AS1	ENST00000659121.1	n.1593-141C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0498 AC: 7581 AN: 152156 Hom.: 363 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.0221

Gnomad FIN AF: 0.0513

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.0463

GnomAD3 exomes AF: 0.0786 AC: 19703 AN: 250578 Hom.: 1680 AF XY: 0.0695 AC XY: 9414 AN XY: 135546

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.239

Gnomad ASJ exome AF: 0.0484

Gnomad EAS exome AF: 0.201

Gnomad SAS exome AF: 0.0184

Gnomad FIN exome AF: 0.0524

Gnomad NFE exome AF: 0.0444

Gnomad OTH exome AF: 0.0662

GnomAD4 exome AF: 0.0527 AC: 77008 AN: 1461490 Hom.: 3412 Cov.: 32 AF XY: 0.0509 AC XY: 36982 AN XY: 727032

Gnomad4 AFR exome AF: 0.00938

Gnomad4 AMR exome AF: 0.227

Gnomad4 ASJ exome AF: 0.0473

Gnomad4 EAS exome AF: 0.189

Gnomad4 SAS exome AF: 0.0197

Gnomad4 FIN exome AF: 0.0546

Gnomad4 NFE exome AF: 0.0450

Gnomad4 OTH exome AF: 0.0514

GnomAD4 genome AF: 0.0498 AC: 7584 AN: 152274 Hom.: 364 Cov.: 32 AF XY: 0.0514 AC XY: 3827 AN XY: 74440

Gnomad4 AFR AF: 0.0116

Gnomad4 AMR AF: 0.138

Gnomad4 ASJ AF: 0.0490

Gnomad4 EAS AF: 0.184

Gnomad4 SAS AF: 0.0215

Gnomad4 FIN AF: 0.0513

Gnomad4 NFE AF: 0.0452

Gnomad4 OTH AF: 0.0449

Alfa AF: 0.0485 Hom.: 197

Bravo AF: 0.0607

TwinsUK AF: 0.0475 AC: 176

ALSPAC AF: 0.0493 AC: 190

ESP6500AA AF: 0.0129 AC: 57

ESP6500EA AF: 0.0433 AC: 372

ExAC AF: 0.0712 AC: 8641

Asia WGS AF: 0.0740 AC: 256 AN: 3478

EpiCase AF: 0.0405

EpiControl AF: 0.0432

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	Sep 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 24, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 19, 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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 23, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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	- -

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. -

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	- -

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. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2012

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	0.22
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	20
Dann	Benign	0.92
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.094
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D;D;D;.;T;D;D;D
MetaRNN	Benign	0.0011	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.3	N;N;.;.;N;N;.;N
REVEL	Benign	0.11
Sift	Benign	0.34	T;T;.;.;T;T;.;T
Polyphen		0.0, 0.0040	.;.;.;B;.;.;B;B
Vest4		0.16
MutPred		0.44		Gain of catalytic residue at L2615 (P = 0.0744);.;Gain of catalytic residue at L2615 (P = 0.0744);Gain of catalytic residue at L2615 (P = 0.0744);.;.;Gain of catalytic residue at L2615 (P = 0.0744);Gain of catalytic residue at L2615 (P = 0.0744);
MPC		0.093
ClinPred		0.0049	T
GERP RS		4.7

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: rs56142888; hg19: chr2-179637861;