Variant chr2-178592175-G-A details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.114465475).

BP6

Variant 2-178592175-G-A is Benign according to our data. Variant chr2-178592175-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178203.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Likely_benign=2, Benign=1}.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.59729C>T	p.Thr19910Ile	missense_variant	302/363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.59729C>T	p.Thr19910Ile	missense_variant	302/363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

14

AN:

151982

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000150

AC:

37

AN:

246908

Hom.:

0

AF XY:

0.000164

AC XY:

22

AN XY:

133970

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000583

Gnomad ASJ exome

AF:

0.00200

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000896

Gnomad OTH exome

AF:

0.000670

GnomAD4 exome

AF:

0.0000760

AC:

111

AN:

1460618

Hom.:

2

Cov.:

35

AF XY:

0.0000895

AC XY:

65

AN XY:

726562

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00211

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.000332

GnomAD4 genome

AF:

0.0000921

AC:

14

AN:

151982

Hom.:

0

Cov.:

32

AF XY:

0.0000943

AC XY:

7

AN XY:

74206

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000293

Hom.:

0

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.00

AC:

0

ESP6500EA

AF:

0.000362

AC:

3

ExAC

AF:

0.0000911

AC:

11

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 17, 2019	- -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 16, 2017	p.Thr17342Ile (c.52025C>T) in exon 251 of the TTN gene (NM_133378.4; Chr2g.179456902G>A). SCICD Classification: variant of uncertain significance, likely benign based on relatively high frequency in the general population, lack of case data and failure to segregate with disease . We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: TTN: TTN encodes titin (also known as connectin), the largest protein in humans; titin plays a critical role in the elastic properties of the sarcomere. Two titin molecules span the sarcomere, anchored at the Z-line and M-line. TTN truncating variants are seen in 13-30% of people with DCM and are thought to confer pathogenesis in a dominant-negative fashion (Herman et al 2012, Roberts et al 2015). There is strong evidence implicating them in the pathogenesis of DCM, though it remains unclear whether they are confer risk in a Mendelian or multifactorial fashion (Watkins et al 2015). Furthermore, each individual TTN variant must be evaluated carefully for potential pathogenicity given the presence of truncating TTN variants in 1-3% of the general population (Herman et al 2012, Roberts et al 2015) and the failure of some TTN truncating variants to segregate in DCM families (Norton et al 2013). Case data (not including our patient): ClinVar: present in 1 lab: Laboratory for Molecular Medicine: 1 patient with DCM who had a pathogenic variant in another gene. Cases in the literature: none reported. Segregation data: none reported. Functional data: none reported. In silico data (missense variants only): Per the test report, "Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. " Conservation data: The threonine at codon 17342 is almost completely conserved across species. Neighboring amino acids are similarly conserved. Nearby pathogenic variants at this codon or neighboring codons: none. Population data: Highest MAF in Ashkenazi Jewish population: 0.18%. The variant was reported online in 33 of 121,946 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 18 of 4,892 individuals of Ashkenazi Jewish descent (MAF=0.18%), 9 of 55,151 individuals of European descent, 2 of 16,689 individuals of Latino descent, 1 of 15,341 individuals of South Asian descent and 3 of 2,703 individuals of "other" descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	TTN: PM2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2021	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 28, 2017	Variant classified as Uncertain Significance - Favor Benign. The p.Thr17342Ile v ariant in TTN has previously been identified by our laboratory in one Caucasian individual with DCM, who also carried a likely pathogenic variant sufficient to explain their disease. This variant has also been identified in 0.18% (18/9784) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http ://gnomad.broadinstitute.org; dbSNP rs369476725). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, tho ugh this information is not predictive enough to determine pathogenicity. In sum mary, while the clinical significance of the Thr17342Ile variant is uncertain, i ts frequency suggests that it is more likely to be benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 10, 2017	- -

Autosomal recessive limb-girdle muscular dystrophy type 2J

Uncertain:1

Uncertain significance, 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, 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. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2017

- -

Dilated cardiomyopathy 1G

Uncertain:1

Uncertain significance, 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, 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 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, 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. -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

TTN-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 30, 2024

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). -

Tibial muscular dystrophy

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. -

Myopathy, myofibrillar, 9, with early respiratory failure

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.12

T

BayesDel_noAF

Benign

-0.22

CADD

Benign

22

DANN

Benign

0.84

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Benign

0.76

T;T;T;.;T;T;T

M_CAP

Benign

0.030

D

MetaRNN

Benign

0.11

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

MetaSVM

Benign

-0.44

T

MutationAssessor

Benign

1.5

.;.;.;L;.;.;L

PrimateAI

Uncertain

0.76

T

PROVEAN

Uncertain

-4.3

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

REVEL

Uncertain

0.45

Sift

Benign

0.11

T;D;.;.;D;D;.

Polyphen

1.0

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

Vest4

0.58

MVP

0.47

MPC

0.47

ClinPred

0.088

T

GERP RS

6.0

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.

chr2-178592175-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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