6-53500221-G-C

Variant names:

• chr6-53500221-G-C
• rs661346
• NM_001498.4:c.1581+26C>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 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=-0.92).
• BP6: Variant 6-53500221-G-C is Benign according to our data. Variant chr6-53500221-G-C is described in ClinVar as Benign. ClinVar VariationId 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.

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.1581+26C>G		intron	N/A	NP_001489.1	P48506
	GCLC	NM_001197115.2		c.1467+26C>G		intron	N/A	NP_001184044.1	E1CEI4
	GCLC-AS1	NR_183318.1		n.327-5933G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLC	ENST00000650454.1	MANE Select	c.1581+26C>G		intron	N/A	ENSP00000497574.1	P48506
	GCLC	ENST00000616923.5	TSL:1	c.1422+26C>G		intron	N/A	ENSP00000482756.2	B4E2I4
	GCLC	ENST00000515580.1	TSL:1	n.1130C>G		non_coding_transcript_exon	Exon 1 of 2

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

GnomAD2 exomes AF: 0.998 AC: 250507 AN: 250976 AF XY: 0.998

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 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

African (AFR) AF: 1.00 AC: 33471 AN: 33474

American (AMR) AF: 0.999 AC: 44669 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.995 AC: 26003 AN: 26126

East Asian (EAS) AF: 1.00 AC: 39698 AN: 39698

South Asian (SAS) AF: 0.994 AC: 85756 AN: 86256

European-Finnish (FIN) AF: 1.00 AC: 53391 AN: 53412

Middle Eastern (MID) AF: 0.992 AC: 5717 AN: 5764

European-Non Finnish (NFE) AF: 0.999 AC: 1110354 AN: 1111556

Other (OTH) AF: 0.998 AC: 60274 AN: 60384

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

African (AFR) AF: 1.00 AC: 41516 AN: 41522

American (AMR) AF: 0.999 AC: 15278 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.995 AC: 3451 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5156 AN: 5156

South Asian (SAS) AF: 0.995 AC: 4797 AN: 4822

European-Finnish (FIN) AF: 1.00 AC: 10613 AN: 10616

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67936 AN: 68030

Other (OTH) AF: 0.999 AC: 2110 AN: 2112

Alfa AF: 0.997 Hom.: 7820

Bravo AF: 0.999

Asia WGS AF: 0.998 AC: 3469 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.067
DANN	Benign	0.42
PhyloP100		-0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs661346; hg19: chr6-53365019;