rs13390491

chr2-178717600-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.25274G>A(p.Ser8425Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 1,612,748 control chromosomes in the GnomAD database, including 24,258 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2432 hom., cov: 32)
  • Exomes 𝑓: 0.16 (21826 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 1.67

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=0.0040527284).
• BP6: Variant 2-178717600-C-T is Benign according to our data. Variant chr2-178717600-C-T is described in ClinVar as [Benign]. Clinvar id is 46756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178717600-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.25274G>A	p.Ser8425Asn	missense_variant	87/363	ENST00000589042.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.25274G>A	p.Ser8425Asn	missense_variant	87/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.503-16904C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25509 AN: 151950 Hom.: 2429 Cov.: 32

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.0987

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.167

GnomAD3 exomes AF: 0.178 AC: 43861 AN: 247098 Hom.: 4660 AF XY: 0.179 AC XY: 23988 AN XY: 134070

Gnomad AFR exome AF: 0.165

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.430

Gnomad SAS exome AF: 0.222

Gnomad FIN exome AF: 0.0955

Gnomad NFE exome AF: 0.150

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.163 AC: 238663 AN: 1460680 Hom.: 21826 Cov.: 35 AF XY: 0.165 AC XY: 119623 AN XY: 726580

Gnomad4 AFR exome AF: 0.167

Gnomad4 AMR exome AF: 0.174

Gnomad4 ASJ exome AF: 0.123

Gnomad4 EAS exome AF: 0.444

Gnomad4 SAS exome AF: 0.220

Gnomad4 FIN exome AF: 0.0933

Gnomad4 NFE exome AF: 0.152

Gnomad4 OTH exome AF: 0.171

GnomAD4 genome AF: 0.168 AC: 25523 AN: 152068 Hom.: 2432 Cov.: 32 AF XY: 0.169 AC XY: 12569 AN XY: 74332

Gnomad4 AFR AF: 0.165

Gnomad4 AMR AF: 0.171

Gnomad4 ASJ AF: 0.126

Gnomad4 EAS AF: 0.431

Gnomad4 SAS AF: 0.223

Gnomad4 FIN AF: 0.0987

Gnomad4 NFE AF: 0.154

Gnomad4 OTH AF: 0.171

Alfa AF: 0.157 Hom.: 3344

Bravo AF: 0.176

TwinsUK AF: 0.149 AC: 554

ALSPAC AF: 0.154 AC: 595

ESP6500AA AF: 0.163 AC: 613

ESP6500EA AF: 0.151 AC: 1242

ExAC AF: 0.176 AC: 21322

Asia WGS AF: 0.325 AC: 1132 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 19, 2012	- -
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	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 23, 2023	Variant summary: TTN c.21542G>A (p.Ser7181Asn) results in a conservative amino acid change located in the I-band (with 4% PSI) of the encoded protein sequence. Three of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.18 in 247098 control chromosomes, predominantly at a frequency of 0.43 within the East Asian subpopulation in the gnomAD database, including 1620 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 700 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.21542G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
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	GeneDx	Oct 31, 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 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	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	- -

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	- -

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

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 21, 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	0.083
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	17
Dann	Benign	0.87
Eigen	Benign	-0.011
Eigen_PC	Benign	0.098
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.65	T;T;.;T
MetaRNN	Benign	0.0041	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.6	N;.;.;.
REVEL	Benign	0.13
Sift	Benign	0.26	T;.;.;.
Polyphen		0.15	.;.;B;B
Vest4		0.080
MPC		0.086
ClinPred		0.0031	T
GERP RS		5.5

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: rs13390491; hg19: chr2-179582327; COSMIC: COSV60101773; COSMIC: COSV60101773;