6-53499011-GTT-GTTTT

Variant names:

• chr6-53499011-G-GTT
• rs17880610
• NM_001498.4:c.1703-46_1703-45dupAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001498.4(GCLC):​c.1703-46_1703-45dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000648 in 956,076 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: GCLC NM_001498.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0660
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1703-46_1703-45dupAA		intron	N/A	NP_001489.1	P48506
	GCLC	NM_001197115.2		c.1589-46_1589-45dupAA		intron	N/A	NP_001184044.1	E1CEI4
	GCLC-AS1	NR_183318.1		n.327-7134_327-7133dupTT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLC	ENST00000650454.1	MANE Select	c.1703-45_1703-44insAA		intron	N/A	ENSP00000497574.1	P48506
	GCLC	ENST00000616923.5	TSL:1	c.1544-45_1544-44insAA		intron	N/A	ENSP00000482756.2	B4E2I4
	GCLC	ENST00000515580.1	TSL:1	n.1307-45_1307-44insAA		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000648 AC: 62 AN: 956076 Hom.: 0 Cov.: 12 AF XY: 0.0000629 AC XY: 31 AN XY: 493140

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000436 AC: 1 AN: 22960

American (AMR) AF: 0.0000255 AC: 1 AN: 39150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21222

East Asian (EAS) AF: 0.00 AC: 0 AN: 33164

South Asian (SAS) AF: 0.00 AC: 0 AN: 70798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4650

European-Non Finnish (NFE) AF: 0.0000862 AC: 58 AN: 673080

Other (OTH) AF: 0.0000471 AC: 2 AN: 42440

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.066

Splicing

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

Other links and lift over

dbSNP: rs17880610; hg19: chr6-53363809;