6-53511293-T-C

Position:

• chr6-53511293-T-C

Variant summary

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

The NM_001498.4(GCLC):​c.754-2043A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 151,856 control chromosomes in the GnomAD database, including 1,601 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 0.14 (1601 hom., cov: 30)
• Consequence: GCLC NM_001498.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.08

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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCLC	NM_001498.4	c.754-2043A>G		intron_variant		ENST00000650454.1
GCLC	NM_001197115.2	c.640-2043A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCLC	ENST00000650454.1	c.754-2043A>G		intron_variant			NM_001498.4	P1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21620 AN: 151738 Hom.: 1599 Cov.: 30

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.141

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

GnomAD4 genome AF: 0.142 AC: 21619 AN: 151856 Hom.: 1601 Cov.: 30 AF XY: 0.142 AC XY: 10518 AN XY: 74200

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.0105

Gnomad4 SAS AF: 0.167

Gnomad4 FIN AF: 0.147

Gnomad4 NFE AF: 0.140

Gnomad4 OTH AF: 0.140

Alfa AF: 0.136 Hom.: 1416

Bravo AF: 0.139

Asia WGS AF: 0.107 AC: 374 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.015
DANN	Benign	0.36

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: rs642429; hg19: chr6-53376091;