rs200594798
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBP6
The NM_001267550.2(TTN):c.21002A>G(p.Lys7001Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,613,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/18 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. K7001K) has been classified as Likely benign.
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.21002A>G | p.Lys7001Arg | missense_variant | 72/363 | ENST00000589042.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.21002A>G | p.Lys7001Arg | missense_variant | 72/363 | 5 | NM_001267550.2 | P1 | |
ENST00000590024.1 | n.917T>C | non_coding_transcript_exon_variant | 1/1 | ||||||
TTN-AS1 | ENST00000659121.1 | n.503-10131T>C | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000644 AC: 98AN: 152138Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000181 AC: 45AN: 248682Hom.: 0 AF XY: 0.000126 AC XY: 17AN XY: 134898
GnomAD4 exome AF: 0.0000808 AC: 118AN: 1461284Hom.: 0 Cov.: 33 AF XY: 0.0000702 AC XY: 51AN XY: 726924
GnomAD4 genome ? AF: 0.000644 AC: 98AN: 152256Hom.: 0 Cov.: 33 AF XY: 0.000645 AC XY: 48AN XY: 74448
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 13, 2022 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 11, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 04, 2021 | This variant is associated with the following publications: (PMID: 23396983) - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 07, 2022 | Variant summary: TTN c.17270A>G (p.Lys5757Arg) results in a conservative amino acid change located in the I-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 0.00018 in 248682 control chromosomes, predominantly at a frequency of 0.0028 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.17270A>G in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely Benign/Benign, n=3; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign. - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 25, 2020 | - - |
Tip-toe gait Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino | - | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at