rs2066508

Variant names:

• chr6-53522444-C-A
• rs2066508
• NM_001498.4:c.234G>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001498.4(GCLC):​c.234G>T​(p.Leu78Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0343 in 1,609,212 control chromosomes in the GnomAD database, including 1,111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (88 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1023 hom.)
• Consequence: GCLC NM_001498.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.578

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 6-53522444-C-A is Benign according to our data. Variant chr6-53522444-C-A is described in ClinVar as [Benign]. Clinvar id is 993340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.578 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0281 (4283/152344) while in subpopulation NFE AF= 0.0407 (2768/68022). AF 95% confidence interval is 0.0394. There are 88 homozygotes in gnomad4. There are 2056 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 88 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCLC	NM_001498.4	c.234G>T	p.Leu78Leu	synonymous_variant	Exon 2 of 16	ENST00000650454.1	NP_001489.1
GCLC	NM_001197115.2	c.234G>T	p.Leu78Leu	synonymous_variant	Exon 2 of 15		NP_001184044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCLC	ENST00000650454.1	c.234G>T	p.Leu78Leu	synonymous_variant	Exon 2 of 16		NM_001498.4	ENSP00000497574.1

Frequencies

GnomAD3 genomes AF: 0.0281 AC: 4283 AN: 152226 Hom.: 88 Cov.: 32

Gnomad AFR AF: 0.00822

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.0249

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.0475

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0407

Gnomad OTH AF: 0.0282

GnomAD3 exomes AF: 0.0270 AC: 6789 AN: 251428 Hom.: 128 AF XY: 0.0272 AC XY: 3703 AN XY: 135896

Gnomad AFR exome AF: 0.00782

Gnomad AMR exome AF: 0.0142

Gnomad ASJ exome AF: 0.0164

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0135

Gnomad FIN exome AF: 0.0455

Gnomad NFE exome AF: 0.0389

Gnomad OTH exome AF: 0.0303

GnomAD4 exome AF: 0.0350 AC: 50934 AN: 1456868 Hom.: 1023 Cov.: 28 AF XY: 0.0346 AC XY: 25100 AN XY: 725156

Gnomad4 AFR exome AF: 0.00610

Gnomad4 AMR exome AF: 0.0148

Gnomad4 ASJ exome AF: 0.0197

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0142

Gnomad4 FIN exome AF: 0.0462

Gnomad4 NFE exome AF: 0.0398

Gnomad4 OTH exome AF: 0.0280

GnomAD4 genome AF: 0.0281 AC: 4283 AN: 152344 Hom.: 88 Cov.: 32 AF XY: 0.0276 AC XY: 2056 AN XY: 74504

Gnomad4 AFR AF: 0.00820

Gnomad4 AMR AF: 0.0248

Gnomad4 ASJ AF: 0.0185

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.0475

Gnomad4 NFE AF: 0.0407

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0361 Hom.: 122

Bravo AF: 0.0247

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0383

EpiControl AF: 0.0373

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GCLC-related disorder Benign:1

Jul 08, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.53
DANN	Benign	0.70

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

Other links and lift over

dbSNP: rs2066508; hg19: chr6-53387242;