rs72648247

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001267550.2(TTN):c.92176C>T(p.Pro30726Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,607,122 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0027 ( 13 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8B:19

Conservation

PhyloP100: 8.15

Variant links:

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 links:

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]

TTN-AS1 links:

ENSG00000270277 (HGNC:):

ENSG00000270277 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008055747).

BP6

Variant 2-178549450-G-A is Benign according to our data. Variant chr2-178549450-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47520.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Likely_pathogenic=1, Benign=5, Uncertain_significance=8}. Variant chr2-178549450-G-A is described in Lovd as [Benign]. Variant chr2-178549450-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00198 (302/152258) while in subpopulation SAS AF= 0.0058 (28/4824). AF 95% confidence interval is 0.00413. There are 3 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.92176C>T	p.Pro30726Ser	missense_variant	Exon 339 of 363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.92176C>T	p.Pro30726Ser	missense_variant	Exon 339 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.00199

AC:

302

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00310

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00268

AC:

659

AN:

245714

Hom.:

AF XY:

0.00307

AC XY:

410

AN XY:

133366

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.000820

Gnomad ASJ exome

AF:

0.00568

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00527

Gnomad FIN exome

AF:

0.00174

Gnomad NFE exome

AF:

0.00329

Gnomad OTH exome

AF:

0.00202

GnomAD4 exome

AF:

0.00274

AC:

3981

AN:

1454864

Hom.:

Cov.:

AF XY:

0.00278

AC XY:

2009

AN XY:

722532

show subpopulations

Gnomad4 AFR exome

AF:

0.000452

Gnomad4 AMR exome

AF:

0.000948

Gnomad4 ASJ exome

AF:

0.00443

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00524

Gnomad4 FIN exome

AF:

0.00124

Gnomad4 NFE exome

AF:

0.00283

Gnomad4 OTH exome

AF:

0.00208

GnomAD4 genome

AF:

0.00198

AC:

302

AN:

152258

Hom.:

Cov.:

AF XY:

0.00216

AC XY:

161

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00580

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.00310

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00287

Hom.:

Bravo

AF:

0.00172

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000524

AC:

ESP6500EA

AF:

0.00230

AC:

ExAC

AF:

0.00245

AC:

296

Asia WGS

AF:

0.00289

AC:

AN:

3476

EpiCase

AF:

0.00295

EpiControl

AF:

0.00261

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:8Benign:19

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24503780) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTN: BS2 -

May 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:6

Mar 30, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Pro28158Ser in exon 288 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.5% (77/15570) of South Asian ch romosomes and 0.3% (199/65938) European chromosomes by the Exome Aggregation Con sortium (ExAC, http://exac.broadinstitute.org; dbSNP rs72648247). -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 04, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TTN c.84472C>T (p.Pro28158Ser) results in a non-conservative amino acid change located in the A-band of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 245714 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 4 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 benign. Co-occurrences with a pathogenic variant has been reported (MYBPC3 c.3628-41_3628-17del25), providing supporting evidence for a benign role. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign n=6, VUS n=2). Based on the evidence outlined above, the variant was classified as benign. -

Jul 31, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Early-onset myopathy with fatal cardiomyopathy

Uncertain:1Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tip-toe gait

Pathogenic:1

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Myopathy refers to diseases that affect skeletal Muscles. These diseases attack muscle fibers, making muscles weak. Inherited myopathies are often caused by inheriting an abnormal gene mutation from a parent that causes the disease. Symptoms of congenital myopathies usually start at birth or in early childhood, but may not appear until the teen years or even later in adulthood. Congenital myopathies are somewhat unique compared with other inherited myopathies, as weakness typically affects all muscles and is often not progressive. Symptoms are: Muscle weakness, most commonly of upper arms and shoulders and thighs, muscle cramps, stiffness and spasms, fatigue with exertion and lack of energy. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

Autosomal recessive limb-girdle muscular dystrophy type 2J

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Limb-girdle muscular dystrophy, recessive

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1G

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dilated Cardiomyopathy, Dominant

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myopathy, myofibrillar, 9, with early respiratory failure

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tibial muscular dystrophy

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TTN-related disorder

Benign:1

Jun 13, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiomyopathy

Benign:1

Oct 28, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Supraventricular tachycardia

Benign:1

Oct 02, 2017

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

May 08, 2023

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

TTN-related myopathy

Benign:1

May 05, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

South Asian population allele frequency is 0.5% (rs72648247, 159/30150 alleles, 1 homozygote in gnomAD v2.1) with a null REVEL score. Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Benign

0.91

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D;D;.;D;D;D

M_CAP

Benign

0.071

MetaRNN

Benign

0.0081

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.36

MutationAssessor

Pathogenic

4.2

.;.;.;H;.;.;H

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.8

D;D;.;.;D;D;.

REVEL

Uncertain

0.52

Sift

Uncertain

0.0050

D;D;.;.;D;D;.

Polyphen

1.0

.;.;.;D;.;.;D

Vest4

0.46

MVP

0.46

MPC

0.47

ClinPred

0.079

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over