rs9474592

chr6-53555418-A-Cchr6-53555418-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000505197.1(GCLC):c.-10+8699T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 151,884 control chromosomes in the GnomAD database, including 8,629 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (8629 hom., cov: 31)
• Consequence: GCLC ENST00000505197.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.347

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCLC	ENST00000505197.1	c.-10+8699T>G		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47557 AN: 151766 Hom.: 8595 Cov.: 31

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.218

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.324

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.314 AC: 47641 AN: 151884 Hom.: 8629 Cov.: 31 AF XY: 0.311 AC XY: 23095 AN XY: 74226

Gnomad4 AFR AF: 0.506

Gnomad4 AMR AF: 0.382

Gnomad4 ASJ AF: 0.236

Gnomad4 EAS AF: 0.298

Gnomad4 SAS AF: 0.219

Gnomad4 FIN AF: 0.183

Gnomad4 NFE AF: 0.215

Gnomad4 OTH AF: 0.320

Alfa AF: 0.113 Hom.: 151

Bravo AF: 0.342

Asia WGS AF: 0.237 AC: 829 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	3.8
Dann	Benign	0.72

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs9474592; hg19: chr6-53420216;