rs2066509
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2
The NM_001498.4(GCLC):c.1563C>T(p.Asp521=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00525 in 1,613,908 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0035 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0054 ( 34 hom. )
Consequence
GCLC
NM_001498.4 synonymous
NM_001498.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 2.78
Genes affected
GCLC (HGNC:4311): (glutamate-cysteine ligase catalytic subunit) Glutamate-cysteine ligase, also known as gamma-glutamylcysteine synthetase is the first rate-limiting enzyme of glutathione synthesis. The enzyme consists of two subunits, a heavy catalytic subunit and a light regulatory subunit. This locus encodes the catalytic subunit, while the regulatory subunit is derived from a different gene located on chromosome 1p22-p21. Mutations at this locus have been associated with hemolytic anemia due to deficiency of gamma-glutamylcysteine synthetase and susceptibility to myocardial infarction.[provided by RefSeq, Oct 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
BP6
?
Variant 6-53500265-G-A is Benign according to our data. Variant chr6-53500265-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 708373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
?
High Homozygotes in GnomAdExome4 at 34 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GCLC | NM_001498.4 | c.1563C>T | p.Asp521= | synonymous_variant | 14/16 | ENST00000650454.1 | |
GCLC-AS1 | NR_183318.1 | n.327-5889G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCLC | ENST00000650454.1 | c.1563C>T | p.Asp521= | synonymous_variant | 14/16 | NM_001498.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00347 AC: 528AN: 152198Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00342 AC: 858AN: 250698Hom.: 6 AF XY: 0.00337 AC XY: 456AN XY: 135460
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GnomAD4 exome AF: 0.00543 AC: 7938AN: 1461592Hom.: 34 Cov.: 33 AF XY: 0.00527 AC XY: 3835AN XY: 727108
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GnomAD4 genome ? AF: 0.00347 AC: 528AN: 152316Hom.: 0 Cov.: 32 AF XY: 0.00325 AC XY: 242AN XY: 74480
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 12, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | GCLC: BP4, BP7, BS2 - |
GCLC-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 05, 2019 | 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). - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at