6-53545239-G-T

Variant names:

• chr6-53545239-G-T
• rs17883901
• ENST00000616923.5:c.-10+2817C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000616923.5(GCLC):​c.-10+2817C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GCLC ENST00000616923.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.743
• Publications: 63 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, Orphanet, Labcorp Genetics (formerly Invitae)
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000616923.5. 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.-594C>A		upstream_gene	N/A	NP_001489.1	P48506
	GCLC	NM_001197115.2		c.-594C>A		upstream_gene	N/A	NP_001184044.1	E1CEI4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLC	ENST00000616923.5	TSL:1	c.-10+2817C>A		intron	N/A	ENSP00000482756.2	B4E2I4
	GCLC	ENST00000505197.1	TSL:4	c.-10+18878C>A		intron	N/A	ENSP00000427403.1	D6RIT4
	GCLC	ENST00000650454.1	MANE Select	c.-594C>A		upstream_gene	N/A	ENSP00000497574.1	P48506

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2222 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 1200

African (AFR) AF: 0.00 AC: 0 AN: 54

American (AMR) AF: 0.00 AC: 0 AN: 32

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 72

East Asian (EAS) AF: 0.00 AC: 0 AN: 208

South Asian (SAS) AF: 0.00 AC: 0 AN: 26

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 8

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1442

Other (OTH) AF: 0.00 AC: 0 AN: 134

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	13
DANN	Benign	0.60
PhyloP100		0.74
PromoterAI		-0.039	Neutral

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs17883901;

hg19: chr6-53410037;