rs670548

Variant names:

• chr6-53502191-C-T
• rs670548
• NM_001498.4:c.1396-1678G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001498.4(GCLC):​c.1396-1678G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.74 in 152,172 control chromosomes in the GnomAD database, including 43,052 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 0.74 (43052 hom., cov: 33)
• Consequence: GCLC NM_001498.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0350
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.919 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.1396-1678G>A		intron	N/A	NP_001489.1
	GCLC	NM_001197115.2		c.1282-1678G>A		intron	N/A	NP_001184044.1
	GCLC-AS1	NR_183318.1		n.327-3963C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLC	ENST00000650454.1	MANE Select	c.1396-1678G>A		intron	N/A	ENSP00000497574.1
	GCLC	ENST00000616923.5	TSL:1	c.1237-1678G>A		intron	N/A	ENSP00000482756.2
	GCLC	ENST00000643939.1		c.1402-1678G>A		intron	N/A	ENSP00000495686.1

Frequencies

GnomAD3 genomes AF: 0.740 AC: 112535 AN: 152054 Hom.: 42976 Cov.: 33

Gnomad AFR AF: 0.927

Gnomad AMI AF: 0.535

Gnomad AMR AF: 0.769

Gnomad ASJ AF: 0.579

Gnomad EAS AF: 0.734

Gnomad SAS AF: 0.821

Gnomad FIN AF: 0.712

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.631

Gnomad OTH AF: 0.707

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

GnomAD4 genome AF: 0.740 AC: 112674 AN: 152172 Hom.: 43052 Cov.: 33 AF XY: 0.746 AC XY: 55487 AN XY: 74396

African (AFR) AF: 0.927 AC: 38527 AN: 41552

American (AMR) AF: 0.770 AC: 11771 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 2010 AN: 3472

East Asian (EAS) AF: 0.734 AC: 3800 AN: 5178

South Asian (SAS) AF: 0.822 AC: 3960 AN: 4818

European-Finnish (FIN) AF: 0.712 AC: 7527 AN: 10572

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.631 AC: 42892 AN: 67964

Other (OTH) AF: 0.711 AC: 1504 AN: 2116

Alfa AF: 0.674 Hom.: 49106

Bravo AF: 0.751

Asia WGS AF: 0.819 AC: 2846 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.4
DANN	Benign	0.77
PhyloP100		0.035
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: rs670548; hg19: chr6-53366989;