rs370135374
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBP6
The NM_001267550.2(TTN):c.54490T>C(p.Tyr18164His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000271 in 1,611,654 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.54490T>C | p.Tyr18164His | missense_variant | 282/363 | ENST00000589042.5 | |
TTN-AS1 | NR_038272.1 | n.3918-534A>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.54490T>C | p.Tyr18164His | missense_variant | 282/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.502+6516A>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000158 AC: 24AN: 151972Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000126 AC: 31AN: 246988Hom.: 0 AF XY: 0.000149 AC XY: 20AN XY: 133968
GnomAD4 exome AF: 0.000282 AC: 412AN: 1459564Hom.: 0 Cov.: 31 AF XY: 0.000281 AC XY: 204AN XY: 726044
GnomAD4 genome ? AF: 0.000158 AC: 24AN: 152090Hom.: 1 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 74332
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 01, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 03, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 15, 2020 | This variant is associated with the following publications: (PMID: 24503780) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 13, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2023 | - - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 28, 2021 | The p.Tyr15596His variant in TTN is classified as likely benign because it has been identified in 0.03% (32/127260) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). It has also been identified by our laboratory in 1 individual with DCM, who carried another likely pathogenic variant in TTN, and in 1 individual with HCM, who also carried a pathogenic variant in PKP2 and a likely pathogenic variant in MYH7 (LMM unpublished data). ACMG/AMP Criteria applied: BS1, BP5. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 29, 2024 | Variant summary: TTN c.46786T>C (p.Tyr15596His) results in a conservative amino acid change located in the A-band region of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 1604706 control chromosomes, predominantly at a frequency of 0.00036 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00027 vs 0.00039), allowing no conclusion about variant significance. c.46786T>C has been reported in the literature in individuals affected with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 47091). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 24, 2017 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 11, 2019 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 25, 2019 | The p.Y9099H variant (also known as c.27295T>C), located in coding exon 109 of the TTN gene, results from a T to C substitution at nucleotide position 27295. The tyrosine at codon 9099 is replaced by histidine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at