rs4894048

Positions:

• chr2-178773994-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.7174G>A​(p.Gly2392Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0405 in 1,613,948 control chromosomes in the GnomAD database, including 2,940 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. G2392G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.060 (427 hom., cov: 32)
  • Exomes 𝑓: 0.039 (2513 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 4.17

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=0.0017631948).
• BP6: Variant 2-178773994-C-T is Benign according to our data. Variant chr2-178773994-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 47377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178773994-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.7174G>A	p.Gly2392Ser	missense_variant	31/363	ENST00000589042.5
TTN	NM_133379.5	c.7174G>A	p.Gly2392Ser	missense_variant	31/46	ENST00000360870.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.7174G>A	p.Gly2392Ser	missense_variant	31/363	5	NM_001267550.2	P1
TTN	ENST00000360870.10	c.7174G>A	p.Gly2392Ser	missense_variant	31/46	5	NM_133379.5
TTN-AS1	ENST00000659121.1	n.1654-233C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0595 AC: 9046 AN: 152024 Hom.: 419 Cov.: 32

Gnomad AFR AF: 0.0920

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.0579

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0223

Gnomad OTH AF: 0.0416

GnomAD3 exomes AF: 0.0700 AC: 17574 AN: 250978 Hom.: 1190 AF XY: 0.0677 AC XY: 9183 AN XY: 135620

Gnomad AFR exome AF: 0.0946

Gnomad AMR exome AF: 0.187

Gnomad ASJ exome AF: 0.0340

Gnomad EAS exome AF: 0.0187

Gnomad SAS exome AF: 0.152

Gnomad FIN exome AF: 0.0561

Gnomad NFE exome AF: 0.0233

Gnomad OTH exome AF: 0.0567

GnomAD4 exome AF: 0.0385 AC: 56347 AN: 1461806 Hom.: 2513 Cov.: 34 AF XY: 0.0408 AC XY: 29663 AN XY: 727214

Gnomad4 AFR exome AF: 0.0929

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.0337

Gnomad4 EAS exome AF: 0.00942

Gnomad4 SAS exome AF: 0.147

Gnomad4 FIN exome AF: 0.0574

Gnomad4 NFE exome AF: 0.0225

Gnomad4 OTH exome AF: 0.0435

GnomAD4 genome AF: 0.0596 AC: 9070 AN: 152142 Hom.: 427 Cov.: 32 AF XY: 0.0644 AC XY: 4787 AN XY: 74384

Gnomad4 AFR AF: 0.0921

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.0314

Gnomad4 EAS AF: 0.0164

Gnomad4 SAS AF: 0.146

Gnomad4 FIN AF: 0.0579

Gnomad4 NFE AF: 0.0223

Gnomad4 OTH AF: 0.0412

Alfa AF: 0.0320 Hom.: 257

Bravo AF: 0.0641

TwinsUK AF: 0.0205 AC: 76

ALSPAC AF: 0.0200 AC: 77

ESP6500AA AF: 0.0951 AC: 419

ESP6500EA AF: 0.0221 AC: 190

ExAC AF: 0.0653 AC: 7925

Asia WGS AF: 0.105 AC: 364 AN: 3478

EpiCase AF: 0.0215

EpiControl AF: 0.0219

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 30, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 20, 2012	Gly2392Ser in exon 31 of TTN: This variant is not expected to have clinical sign ificance because it has been identified in 9.6% of African American chromosomes from a broad population by NHLBI Exome Sequencing Project (http://evs.gs.washing ton.edu/EVS/dbSNP rs4894048). -
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	GeneDx	Oct 26, 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, 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	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Early-onset myopathy with fatal cardiomyopathy Benign:2

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. -
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	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Tibial muscular dystrophy Benign:2

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. -
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 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

Jun 18, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 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	0.13
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.94
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.74	T;T;T;.;T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationTaster	Benign	0.74	P;P;P;P;P;P;P
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.8	D;D;.;.;D;D;.;D
REVEL	Uncertain	0.57
Sift	Benign	0.033	D;D;.;.;D;D;.;D
Polyphen		0.99, 1.0	.;.;.;D;.;.;D;D
Vest4		0.071
MPC		0.24
ClinPred		0.041	T
GERP RS		4.9

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: rs4894048; hg19: chr2-179638721;