rs600033

Positions:

• chr6-53517572-G-C
• chr6-53517572-G-T

Variant summary

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

The NM_001498.4(GCLC):​c.447-1350C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 151,920 control chromosomes in the GnomAD database, including 15,348 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 0.45 (15348 hom., cov: 31)
• Consequence: GCLC NM_001498.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.777

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=-0.95).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.542 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCLC	NM_001498.4	c.447-1350C>G		intron_variant		ENST00000650454.1
GCLC	NM_001197115.2	c.447-3075C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCLC	ENST00000650454.1	c.447-1350C>G		intron_variant			NM_001498.4	P1

Frequencies

GnomAD3 genomes AF: 0.445 AC: 67604 AN: 151800 Hom.: 15333 Cov.: 31

Gnomad AFR AF: 0.369

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.551

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.519

Gnomad FIN AF: 0.455

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.465

Gnomad OTH AF: 0.451

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

GnomAD4 genome AF: 0.445 AC: 67641 AN: 151920 Hom.: 15348 Cov.: 31 AF XY: 0.448 AC XY: 33276 AN XY: 74256

Gnomad4 AFR AF: 0.368

Gnomad4 AMR AF: 0.551

Gnomad4 ASJ AF: 0.406

Gnomad4 EAS AF: 0.417

Gnomad4 SAS AF: 0.519

Gnomad4 FIN AF: 0.455

Gnomad4 NFE AF: 0.465

Gnomad4 OTH AF: 0.455

Alfa AF: 0.443 Hom.: 1823

Bravo AF: 0.449

Asia WGS AF: 0.463 AC: 1611 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.36
DANN	Benign	0.43

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: rs600033; hg19: chr6-53382370; COSMIC: COSV57594779; COSMIC: COSV57594779;