rs72650031

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001267550.2(TTN):c.32624C>T(p.Pro10875Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00606 in 1,609,214 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0044 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0062 ( 51 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:21

Conservation

PhyloP100: 1.50

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:

LOC124906100 (HGNC:):

LOC124906100 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 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=0.0047104955).

BP6

Variant 2-178684680-G-A is Benign according to our data. Variant chr2-178684680-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46873.We mark this variant Likely_benign, oryginal submissions are: {Benign=11, Likely_benign=6, Uncertain_significance=2}. Variant chr2-178684680-G-A is described in Lovd as [Benign]. Variant chr2-178684680-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00442 (672/152134) while in subpopulation NFE AF= 0.00611 (415/67952). AF 95% confidence interval is 0.00562. There are 4 homozygotes in gnomad4. There are 318 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.32624C>T	p.Pro10875Leu	missense_variant	131/363	ENST00000589042.5
LOC124906100	XR_007087318.1 linkuse as main transcript	n.2186-29074G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.32624C>T	p.Pro10875Leu	missense_variant	131/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.503-49824G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00442

AC:

672

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00512

Gnomad ASJ

AF:

0.0271

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00611

Gnomad OTH

AF:

0.00672

GnomAD3 exomes

AF:

0.00544

AC:

1329

AN:

244514

Hom.:

AF XY:

0.00542

AC XY:

718

AN XY:

132546

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00503

Gnomad ASJ exome

AF:

0.0315

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00173

Gnomad FIN exome

AF:

0.000793

Gnomad NFE exome

AF:

0.00650

Gnomad OTH exome

AF:

0.00623

GnomAD4 exome

AF:

0.00623

AC:

9080

AN:

1457080

Hom.:

Cov.:

AF XY:

0.00624

AC XY:

4519

AN XY:

724646

show subpopulations

Gnomad4 AFR exome

AF:

0.00109

Gnomad4 AMR exome

AF:

0.00484

Gnomad4 ASJ exome

AF:

0.0298

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00189

Gnomad4 FIN exome

AF:

0.000769

Gnomad4 NFE exome

AF:

0.00658

Gnomad4 OTH exome

AF:

0.00785

GnomAD4 genome

AF:

0.00442

AC:

672

AN:

152134

Hom.:

Cov.:

AF XY:

0.00427

AC XY:

318

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.00511

Gnomad4 ASJ

AF:

0.0271

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00611

Gnomad4 OTH

AF:

0.00665

Alfa

AF:

0.00716

Hom.:

Bravo

AF:

0.00465

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000818

AC:

ESP6500EA

AF:

0.00588

AC:

ExAC

AF:

0.00504

AC:

609

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00927

EpiControl

AF:

0.00937

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:21

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:9

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 13, 2019	Variant summary: TTN c.28892C>T (p.Pro9631Leu) results in a non-conservative amino acid change located in the I-band region of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0054 in 244514 control chromosomes, predominantly at a frequency of 0.0065 within the Non-Finnish European subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 10 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 Non-Finnish European origin. c.28892C>T has been reported in the literature in individuals affected with hypertrophic and dilated Cardiomyopathies (HCM/DCM) as well as ARVC, SUD, SUD/SIDS and CPVT (Pugh_2014, Lopes_2013, Campuzano_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with other pathogenic variant(s) that explained the clinical indication of testing have been reported (TTN c.81493_81493+2delGGT, p.?, Pugh_2014; and MYH7 c.1063G>A, p.Ala355Thr, Lopes_2013), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Six of these submitters reported a classification as benign (n=3)/likely benign (n=3). Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2016	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, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 31, 2019	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 16, 2015	p.Pro9631Leu in exon 128 of TTN: This variant is not expected to have clinical s ignificance because it has been identified in 0.8% (510/66482) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs72650031). -
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	Eurofins Ntd Llc (ga)	Aug 01, 2015	- -

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 10, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 28, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TTN: BP4, BS2 -

Autosomal recessive limb-girdle muscular dystrophy type 2J

Uncertain:1

Uncertain significance, 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, 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. -

Early-onset myopathy with fatal cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Dilated cardiomyopathy 1G

Benign:1

Likely 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 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

Jun 26, 2018

- -

Supraventricular tachycardia;C0042514:Ventricular tachycardia;C1142166:Brugada syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Mar 26, 2019

- -

Tibial muscular dystrophy

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. -

Myopathy, myofibrillar, 9, with early respiratory failure

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. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 2012

This alteration is classified as likely 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

0.12

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.83

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.0064

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.67

T;T;.;T

M_CAP

Benign

0.068

MetaRNN

Benign

0.0047

T;T;T;T

MetaSVM

Benign

-0.89

MutationTaster

Benign

0.95

D;D;D;D;D;N

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-4.2

D;.;.;.

REVEL

Benign

0.099

Sift

Uncertain

0.018

D;.;.;.

Polyphen

0.0010

.;.;B;B

Vest4

0.31

MVP

0.40

MPC

0.085

ClinPred

0.015

GERP RS

4.8

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

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