rs72648237
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_001267550.2(TTN):c.89386G>A(p.Val29796Met) variant causes a missense change. The variant allele was found at a frequency of 0.000965 in 1,613,874 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V29796V) has been classified as Likely benign.
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.89386G>A | p.Val29796Met | missense_variant | 334/363 | ENST00000589042.5 | |
TTN-AS1 | NR_038272.1 | n.2043+11258C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.89386G>A | p.Val29796Met | missense_variant | 334/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.416+29983C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000756 AC: 115AN: 152176Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.00128 AC: 319AN: 248568Hom.: 3 AF XY: 0.00164 AC XY: 221AN XY: 134822
GnomAD4 exome AF: 0.000987 AC: 1443AN: 1461580Hom.: 4 Cov.: 33 AF XY: 0.00113 AC XY: 822AN XY: 727072
GnomAD4 genome ? AF: 0.000749 AC: 114AN: 152294Hom.: 1 Cov.: 33 AF XY: 0.000685 AC XY: 51AN XY: 74468
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 16, 2018 | This variant is associated with the following publications: (PMID: 23396983, 23861362) - |
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | TTN: BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 28, 2023 | - - |
not specified Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 02, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 09, 2015 | p.Val27228Met in exon 283 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.5% (89/16510) of South Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs72648237). - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 22, 2022 | - - |
Hypertrophic cardiomyopathy Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Jul 26, 2017 | - - |
Likely benign, criteria provided, single submitter | research | Genetics and Genomics Program, Sidra Medicine | - | - - |
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 | 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. - |
Dilated cardiomyopathy 1G 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. - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Genetics and Genomics Program, Sidra Medicine | - | - - |
TTN-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 14, 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). - |
Cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Feb 09, 2018 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Hypotonia;C0037822:Abnormality of speech or vocalization;C0349588:Short stature;C0454644:Delayed speech and language development;C0746674:Generalized muscle weakness;C2315100:Failure to thrive;C4021753:Abnormality of the immune system Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Mar 21, 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 | Jun 07, 2019 | Subpopulation frequency in support of benign classification - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at