Genetic Variant GCLC:c.1703-46_1703-45delAA (chr6-53499011-GTT-G) – ACMG Classification: Uncertain_significance (2 pts)

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_1703-45delAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000452 in 1,106,230 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: 𝑓 0.0000067 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

GCLC
NM_001498.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0660

Publications

0 publications found

Variant links:

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 links:

GCLC-AS1 (HGNC:56649): (GCLC antisense RNA 1)

GCLC-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GCLC	NM_001498.4	MANE Select	c.1703-46_1703-45delAA	intron	N/A	NP_001489.1	P48506
GCLC	NM_001197115.2		c.1589-46_1589-45delAA	intron	N/A	NP_001184044.1	E1CEI4
GCLC-AS1	NR_183318.1		n.327-7134_327-7133delTT	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GCLC	ENST00000650454.1	MANE Select	c.1703-46_1703-45delAA	intron	N/A	ENSP00000497574.1	P48506
GCLC	ENST00000616923.5	TSL:1	c.1544-46_1544-45delAA	intron	N/A	ENSP00000482756.2	B4E2I4
GCLC	ENST00000515580.1	TSL:1	n.1307-46_1307-45delAA	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00000668

AC:

AN:

149678

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000418

AC:

AN:

956552

Hom.:

AF XY:

0.00000608

AC XY:

AN XY:

493354

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

22978

American (AMR)

AF:

0.00

AC:

AN:

39172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21228

East Asian (EAS)

AF:

0.00

AC:

AN:

33176

South Asian (SAS)

AF:

0.00

AC:

AN:

70808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48638

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4652

European-Non Finnish (NFE)

AF:

0.00000594

AC:

AN:

673438

Other (OTH)

AF:

0.00

AC:

AN:

42462

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000521060), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.300

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000668

AC:

AN:

149678

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72894

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40690

American (AMR)

AF:

0.00

AC:

AN:

15016

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3444

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.00

AC:

AN:

4716

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10140

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

67262

Other (OTH)

AF:

0.00

AC:

AN:

2054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

107

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.066

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over