chr6-53500265-G-A

Variant names:

• chr6-53500265-G-A
• rs2066509
• NM_001498.4:c.1563C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001498.4(GCLC):​c.1563C>T​(p.Asp521Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00525 in 1,613,908 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (34 hom.)
• Consequence: GCLC NM_001498.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.78
• Publications: 6 publications found

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:56649): (GCLC antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 6-53500265-G-A is Benign according to our data. Variant chr6-53500265-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 708373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 34 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001498.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLC	NM_001498.4	MANE Select	c.1563C>T	p.Asp521Asp	synonymous	Exon 14 of 16	NP_001489.1	P48506
	GCLC	NM_001197115.2		c.1449C>T	p.Asp483Asp	synonymous	Exon 13 of 15	NP_001184044.1	E1CEI4
	GCLC-AS1	NR_183318.1		n.327-5889G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLC	ENST00000650454.1	MANE Select	c.1563C>T	p.Asp521Asp	synonymous	Exon 14 of 16	ENSP00000497574.1	P48506
	GCLC	ENST00000616923.5	TSL:1	c.1404C>T	p.Asp468Asp	synonymous	Exon 14 of 16	ENSP00000482756.2	B4E2I4
	GCLC	ENST00000515580.1	TSL:1	n.1086C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00347 AC: 528 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00660

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00342 AC: 858 AN: 250698 AF XY: 0.00337

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.000796

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00282

Gnomad NFE exome AF: 0.00641

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00543 AC: 7938 AN: 1461592 Hom.: 34 Cov.: 33 AF XY: 0.00527 AC XY: 3835 AN XY: 727108

African (AFR) AF: 0.000747 AC: 25 AN: 33472

American (AMR) AF: 0.000671 AC: 30 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000533 AC: 46 AN: 86254

European-Finnish (FIN) AF: 0.00245 AC: 131 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00671 AC: 7464 AN: 1111740

Other (OTH) AF: 0.00371 AC: 224 AN: 60386

GnomAD4 genome AF: 0.00347 AC: 528 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.00325 AC XY: 242 AN XY: 74480

African (AFR) AF: 0.00120 AC: 50 AN: 41576

American (AMR) AF: 0.000850 AC: 13 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00660 AC: 449 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00529 Hom.: 11

Bravo AF: 0.00308

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00676

EpiControl AF: 0.00533

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	GCLC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.9
DANN	Benign	0.82
PhyloP100		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs2066509; hg19: chr6-53365063; COSMIC: COSV105851156; COSMIC: COSV105851156;