rs1552280

chr2-178779308-G-Achr2-178779308-G-C

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.3884C>T(p.Ser1295Leu) variant causes a missense change. The variant allele was found at a frequency of 0.978 in 1,613,600 control chromosomes in the GnomAD database, including 772,469 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (68587 hom., cov: 32)
  • Exomes 𝑓: 0.98 (703882 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 6.29

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]

LOC101927055 (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=6.196605E-7).
• BP6: Variant 2-178779308-G-A is Benign according to our data. Variant chr2-178779308-G-A is described in ClinVar as [Benign]. Clinvar id is 47001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178779308-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.3884C>T	p.Ser1295Leu	missense_variant	23/363	ENST00000589042.5
TTN	NM_133379.5	c.3884C>T	p.Ser1295Leu	missense_variant	23/46	ENST00000360870.10
LOC101927055	NR_120594.1	n.1831-530G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.3884C>T	p.Ser1295Leu	missense_variant	23/363	5	NM_001267550.2	P1
TTN	ENST00000360870.10	c.3884C>T	p.Ser1295Leu	missense_variant	23/46	5	NM_133379.5
TTN-AS1	ENST00000659121.1	n.6183-530G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.948 AC: 144176 AN: 152132 Hom.: 68561 Cov.: 32

Gnomad AFR AF: 0.869

Gnomad AMI AF: 0.843

Gnomad AMR AF: 0.964

Gnomad ASJ AF: 0.994

Gnomad EAS AF: 0.872

Gnomad SAS AF: 0.951

Gnomad FIN AF: 0.980

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.991

Gnomad OTH AF: 0.948

GnomAD3 exomes AF: 0.962 AC: 240635 AN: 250190 Hom.: 115921 AF XY: 0.965 AC XY: 130580 AN XY: 135248

Gnomad AFR exome AF: 0.869

Gnomad AMR exome AF: 0.939

Gnomad ASJ exome AF: 0.992

Gnomad EAS exome AF: 0.881

Gnomad SAS exome AF: 0.958

Gnomad FIN exome AF: 0.978

Gnomad NFE exome AF: 0.990

Gnomad OTH exome AF: 0.970

GnomAD4 exome AF: 0.981 AC: 1433607 AN: 1461350 Hom.: 703882 Cov.: 54 AF XY: 0.981 AC XY: 713137 AN XY: 726998

Gnomad4 AFR exome AF: 0.866

Gnomad4 AMR exome AF: 0.943

Gnomad4 ASJ exome AF: 0.993

Gnomad4 EAS exome AF: 0.870

Gnomad4 SAS exome AF: 0.958

Gnomad4 FIN exome AF: 0.977

Gnomad4 NFE exome AF: 0.992

Gnomad4 OTH exome AF: 0.971

GnomAD4 genome AF: 0.947 AC: 144254 AN: 152250 Hom.: 68587 Cov.: 32 AF XY: 0.948 AC XY: 70544 AN XY: 74432

Gnomad4 AFR AF: 0.868

Gnomad4 AMR AF: 0.964

Gnomad4 ASJ AF: 0.994

Gnomad4 EAS AF: 0.872

Gnomad4 SAS AF: 0.951

Gnomad4 FIN AF: 0.980

Gnomad4 NFE AF: 0.991

Gnomad4 OTH AF: 0.948

Alfa AF: 0.980 Hom.: 120312

Bravo AF: 0.940

TwinsUK AF: 0.992 AC: 3680

ALSPAC AF: 0.992 AC: 3825

ESP6500AA AF: 0.872 AC: 3841

ESP6500EA AF: 0.991 AC: 8524

ExAC AF: 0.960 AC: 116549

Asia WGS AF: 0.907 AC: 3156 AN: 3478

EpiCase AF: 0.991

EpiControl AF: 0.991

ClinVar

Significance: Benign

Submissions summary: Benign:24

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:12

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2013	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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic 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 13, 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	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

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 13, 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 13, 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

Jan 15, 2019

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 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	0.036
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	21
Dann	Benign	0.97
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.084	T;T;T;.;T;T;T;T
MetaRNN	Benign	6.2e-7	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	2.2	N;N;.;.;N;N;.;N
REVEL	Benign	0.18
Sift	Benign	0.33	T;T;.;.;T;T;.;T
Polyphen		0.0	.;.;.;B;.;.;B;B
Vest4		0.038
MPC		0.074
ClinPred		0.017	T
GERP RS		5.7

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: rs1552280; hg19: chr2-179644035;