2-178777224-G-A

Position:

• chr2-178777224-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.4739C>T​(p.Thr1580Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,614,072 control chromosomes in the GnomAD database, including 15 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (7 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 2.60

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 in gene, where missense usually causes diseases (based on misZ statistic), TTN. . Gene score misZ -1.1021 (greater than the threshold 3.09). Trascript score misZ 6.9794 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, tibial muscular dystrophy, early-onset myopathy with fatal cardiomyopathy, autosomal recessive centronuclear myopathy, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 9, TTN-related myopathy, dilated cardiomyopathy 1G, arrhythmogenic right ventricular cardiomyopathy, myopathy, myofibrillar, 9, with early respiratory failure, familial isolated dilated cardiomyopathy, childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome, autosomal recessive limb-girdle muscular dystrophy type 2J.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0056105256).
• BP6: Variant 2-178777224-G-A is Benign according to our data. Variant chr2-178777224-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 47100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178777224-G-A is described in Lovd as [Benign]. Variant chr2-178777224-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00512 (780/152282) while in subpopulation AFR AF= 0.017 (708/41550). AF 95% confidence interval is 0.016. There are 8 homozygotes in gnomad4. There are 377 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.4739C>T	p.Thr1580Met	missense_variant	27/363	ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.4739C>T	p.Thr1580Met	missense_variant	27/46	ENST00000360870.10	NP_596870.2
LOC101927055	NR_120594.1	n.299G>A		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.4739C>T	p.Thr1580Met	missense_variant	27/363	5	NM_001267550.2	ENSP00000467141	P1
TTN	ENST00000360870.10	c.4739C>T	p.Thr1580Met	missense_variant	27/46	5	NM_133379.5	ENSP00000354117
TTN-AS1	ENST00000659121.1	n.4651G>A		non_coding_transcript_exon_variant	12/13

Frequencies

GnomAD3 genomes AF: 0.00511 AC: 778 AN: 152164 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00141 AC: 355 AN: 251036 Hom.: 3 AF XY: 0.00106 AC XY: 144 AN XY: 135660

Gnomad AFR exome AF: 0.0182

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000882

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000657 AC: 961 AN: 1461790 Hom.: 7 Cov.: 33 AF XY: 0.000637 AC XY: 463 AN XY: 727204

Gnomad4 AFR exome AF: 0.0193

Gnomad4 AMR exome AF: 0.000962

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000130

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00512 AC: 780 AN: 152282 Hom.: 8 Cov.: 32 AF XY: 0.00506 AC XY: 377 AN XY: 74456

Gnomad4 AFR AF: 0.0170

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000912 Hom.: 2

Bravo AF: 0.00587

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0159 AC: 70

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00174 AC: 211

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:25

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 24, 2012	Thr1580Met in exon 27 of TTN: This variant is classified as benign based on its high frequency in the general population (NHLBI Exome Sequencing Project, http:/ /evs.gs.washington.edu/EVS; dbSNP rs179641951). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2014	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. -

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 09, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Nov 28, 2018	- -

Early-onset myopathy with fatal cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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 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. -

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. -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Dilated cardiomyopathy 1G Benign:1

Likely 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 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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 18, 2013

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	0.074
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.86
Eigen	Benign	-0.078
Eigen_PC	Benign	0.020
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.89	D;D;D;.;D;D;D;D
MetaRNN	Benign	0.0056	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.8	D;D;.;.;D;D;.;D
REVEL	Benign	0.15
Sift	Uncertain	0.013	D;T;.;.;T;T;.;D
Sift4G	Uncertain	0.033	.;.;.;.;.;.;.;D
Polyphen		0.0070, 0.068	.;.;.;B;.;.;B;B
Vest4		0.13
MVP		0.46
MPC		0.089
ClinPred		0.018	T
GERP RS		2.8

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: rs73973147; hg19: chr2-179641951; COSMIC: COSV59898034; COSMIC: COSV59898034;