chr2-178764191-C-T

Position:

• chr2-178764191-C-T

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.10100G>A​(p.Arg3367Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,614,078 control chromosomes in the GnomAD database, including 197 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 0.0096 (10 hom., cov: 33)
  • Exomes 𝑓: 0.015 (187 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 0.765

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 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=0.0077604353).
• BP6: Variant 2-178764191-C-T is Benign according to our data. Variant chr2-178764191-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178764191-C-T is described in Lovd as [Benign]. Variant chr2-178764191-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00961 (1463/152276) while in subpopulation NFE AF= 0.0157 (1069/68028). AF 95% confidence interval is 0.0149. There are 10 homozygotes in gnomad4. There are 680 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.10100G>A	p.Arg3367Gln	missense_variant	43/363	ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.10100G>A	p.Arg3367Gln	missense_variant	43/46	ENST00000360870.10	NP_596870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.10100G>A	p.Arg3367Gln	missense_variant	43/363	5	NM_001267550.2	ENSP00000467141	P1
TTN	ENST00000360870.10	c.10100G>A	p.Arg3367Gln	missense_variant	43/46	5	NM_133379.5	ENSP00000354117
TTN-AS1	ENST00000659121.1	n.1415C>T		non_coding_transcript_exon_variant	10/13

Frequencies

GnomAD3 genomes AF: 0.00962 AC: 1463 AN: 152158 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00603

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0157

Gnomad OTH AF: 0.00910

GnomAD3 exomes AF: 0.0102 AC: 2554 AN: 251330 Hom.: 21 AF XY: 0.0110 AC XY: 1492 AN XY: 135814

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00489

Gnomad ASJ exome AF: 0.0225

Gnomad EAS exome AF: 0.000980

Gnomad SAS exome AF: 0.00673

Gnomad FIN exome AF: 0.00212

Gnomad NFE exome AF: 0.0156

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0153 AC: 22341 AN: 1461802 Hom.: 187 Cov.: 32 AF XY: 0.0152 AC XY: 11036 AN XY: 727206

Gnomad4 AFR exome AF: 0.00260

Gnomad4 AMR exome AF: 0.00557

Gnomad4 ASJ exome AF: 0.0223

Gnomad4 EAS exome AF: 0.00128

Gnomad4 SAS exome AF: 0.00716

Gnomad4 FIN exome AF: 0.00264

Gnomad4 NFE exome AF: 0.0177

Gnomad4 OTH exome AF: 0.0149

GnomAD4 genome AF: 0.00961 AC: 1463 AN: 152276 Hom.: 10 Cov.: 33 AF XY: 0.00913 AC XY: 680 AN XY: 74452

Gnomad4 AFR AF: 0.00301

Gnomad4 AMR AF: 0.00602

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00767

Gnomad4 FIN AF: 0.00302

Gnomad4 NFE AF: 0.0157

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.0153 Hom.: 35

Bravo AF: 0.0104

TwinsUK AF: 0.0165 AC: 61

ALSPAC AF: 0.0202 AC: 78

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0164 AC: 141

ExAC AF: 0.00996 AC: 1209

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0159

EpiControl AF: 0.0164

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:25

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 12, 2012	Arg3367Gln in Exon 43 of TTN: This variant is not expected to have clinical sign ificance because it has been identified in 1.6% (114/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs34819099). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 03, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
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	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 24, 2020	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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

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

Early-onset myopathy with fatal cardiomyopathy Benign:2

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. -
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 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	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 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. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 10, 2022

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 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	0.088
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Uncertain	0.98
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.84	T;T;T;.;T;T;T;T
MetaRNN	Benign	0.0078	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.3	N;N;.;.;N;N;.;N
REVEL	Benign	0.051
Sift	Benign	0.30	T;T;.;.;T;T;.;T
Sift4G	Benign	0.20	.;.;.;.;.;.;.;T
Polyphen		0.0050, 0.063	.;.;.;B;.;.;B;B
Vest4		0.21
MPC		0.097
ClinPred		0.0083	T
GERP RS		1.3

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: rs34819099; hg19: chr2-179628918;