Genetic Variant GCLC:c.-10+2817C>T (chr6-53545239-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000616923.5(GCLC):c.-10+2817C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0637 in 154,512 control chromosomes in the GnomAD database, including 344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.063 ( 337 hom., cov: 32)

Exomes 𝑓: 0.081 ( 7 hom. )

Consequence

GCLC
ENST00000616923.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 0.743

Publications

63 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 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

GCLC links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript ENST00000616923.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 6-53545239-G-A is Benign according to our data. Variant chr6-53545239-G-A is described in ClinVar as Benign. ClinVar VariationId is 439753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

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>T		upstream_gene	N/A	NP_001489.1	P48506
	GCLC	NM_001197115.2		c.-594C>T		upstream_gene	N/A	NP_001184044.1	E1CEI4

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

AF:

0.0635

AC:

9664

AN:

152180

Hom.:

337

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0254

Gnomad AMI

AF:

0.0833

Gnomad AMR

AF:

0.0545

Gnomad ASJ

AF:

0.100

Gnomad EAS

AF:

0.124

Gnomad SAS

AF:

0.0654

Gnomad FIN

AF:

0.0625

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.0813

Gnomad OTH

AF:

0.0776

GnomAD4 exome

AF:

0.0808

AC:

179

AN:

2216

Hom.:

AF XY:

0.0778

AC XY:

AN XY:

1196

show subpopulations

African (AFR)

AF:

0.0185

AC:

AN:

American (AMR)

AF:

0.0313

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.0694

AC:

AN:

East Asian (EAS)

AF:

0.159

AC:

AN:

208

South Asian (SAS)

AF:

0.0769

AC:

AN:

European-Finnish (FIN)

AF:

0.0615

AC:

AN:

244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0813

AC:

117

AN:

1440

Other (OTH)

AF:

0.0379

AC:

AN:

132

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

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:

0.0634

AC:

9662

AN:

152296

Hom.:

337

Cov.:

AF XY:

0.0628

AC XY:

4677

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0253

AC:

1053

AN:

41570

American (AMR)

AF:

0.0545

AC:

834

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.100

AC:

348

AN:

3470

East Asian (EAS)

AF:

0.124

AC:

641

AN:

5170

South Asian (SAS)

AF:

0.0649

AC:

313

AN:

4826

European-Finnish (FIN)

AF:

0.0625

AC:

663

AN:

10614

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0813

AC:

5531

AN:

68020

Other (OTH)

AF:

0.0791

AC:

167

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

480

960

1440

1920

2400

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<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:

0.0663

Hom.:

174

Bravo

AF:

0.0622

Asia WGS

AF:

0.106

AC:

369

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Myocardial infarction, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

(source)

DANN

Benign

0.83

PhyloP100

0.74

PromoterAI

0.080

Neutral

(source)

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.

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