6-53500221-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001498.4(GCLC):c.1581+26C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.999 in 1,613,622 control chromosomes in the GnomAD database, including 804,592 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 1.0 (75949 hom., cov: 29)
  • Exomes 𝑓: 1.0 (728643 hom.)
• Consequence: GCLC NM_001498.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.819

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]

GCLC-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-53500221-G-C is Benign according to our data. Variant chr6-53500221-G-C is described in ClinVar as [Benign]. Clinvar id is 1229628.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCLC	NM_001498.4	c.1581+26C>G		intron_variant		ENST00000650454.1
GCLC-AS1	NR_183318.1	n.327-5933G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCLC	ENST00000650454.1	c.1581+26C>G		intron_variant			NM_001498.4	P1

Frequencies

GnomAD3 genomes AF: 0.999 AC: 151944 AN: 152110 Hom.: 75890 Cov.: 29

Gnomad AFR AF: 1.00

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.999

Gnomad ASJ AF: 0.995

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.995

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.999

GnomAD3 exomes AF: 0.998 AC: 250507 AN: 250976 Hom.: 125024 AF XY: 0.998 AC XY: 135280 AN XY: 135594

Gnomad AFR exome AF: 1.00

Gnomad AMR exome AF: 0.999

Gnomad ASJ exome AF: 0.996

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.995

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.999 AC: 1459333 AN: 1461394 Hom.: 728643 Cov.: 42 AF XY: 0.998 AC XY: 725901 AN XY: 727054

Gnomad4 AFR exome AF: 1.00

Gnomad4 AMR exome AF: 0.999

Gnomad4 ASJ exome AF: 0.995

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.994

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.999

Gnomad4 OTH exome AF: 0.998

GnomAD4 genome AF: 0.999 AC: 152062 AN: 152228 Hom.: 75949 Cov.: 29 AF XY: 0.999 AC XY: 74350 AN XY: 74432

Gnomad4 AFR AF: 1.00

Gnomad4 AMR AF: 0.999

Gnomad4 ASJ AF: 0.995

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.995

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.999

Alfa AF: 0.997 Hom.: 7820

Bravo AF: 0.999

Asia WGS AF: 0.998 AC: 3469 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.067
Dann	Benign	0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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: rs661346; hg19: chr6-53365019;