rs9474592

Variant names:

• chr6-53555418-A-C
• rs9474592
• ENST00000505197.1:c.-10+8699T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-53555418-A-C
• chr6-53555418-A-G

Variant summary

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

The ENST00000505197.1(GCLC):​c.-10+8699T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 151,884 control chromosomes in the GnomAD database, including 8,629 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 0.31 (8629 hom., cov: 31)
• Consequence: GCLC ENST00000505197.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.347
• Publications: 3 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 Gene-Disease associations (from GenCC):

• gamma-glutamylcysteine synthetase deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCLC	ENST00000505197.1	c.-10+8699T>G		intron_variant	Intron 3 of 3	4		ENSP00000427403.1

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47557 AN: 151766 Hom.: 8595 Cov.: 31

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.218

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.324

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

GnomAD4 genome AF: 0.314 AC: 47641 AN: 151884 Hom.: 8629 Cov.: 31 AF XY: 0.311 AC XY: 23095 AN XY: 74226

African (AFR) AF: 0.506 AC: 20920 AN: 41364

American (AMR) AF: 0.382 AC: 5828 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 817 AN: 3464

East Asian (EAS) AF: 0.298 AC: 1537 AN: 5156

South Asian (SAS) AF: 0.219 AC: 1056 AN: 4814

European-Finnish (FIN) AF: 0.183 AC: 1940 AN: 10578

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.215 AC: 14576 AN: 67938

Other (OTH) AF: 0.320 AC: 674 AN: 2108

Alfa AF: 0.113 Hom.: 151

Bravo AF: 0.342

Asia WGS AF: 0.237 AC: 829 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.8
DANN	Benign	0.72
PhyloP100		0.35

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9474592; hg19: chr6-53420216;