Genetic Variant GCLC:c.1703-8G>A (chr6-53498975-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_001498.4(GCLC):c.1703-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000582 in 1,592,652 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00045 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 0 hom. )

Consequence

GCLC
NM_001498.4 splice_region, intron

Scores

Splicing: ADA: 0.0002488

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.27

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: Benign. The variant received -12 ACMG points.

BP4

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

BP6

Variant 6-53498975-C-T is Benign according to our data. Variant chr6-53498975-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1330719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1703-8G>A	splice_region intron	N/A	NP_001489.1	P48506
GCLC	NM_001197115.2		c.1589-8G>A	splice_region intron	N/A	NP_001184044.1	E1CEI4
GCLC-AS1	NR_183318.1		n.327-7179C>T	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GCLC	ENST00000650454.1	MANE Select	c.1703-8G>A	splice_region intron	N/A	ENSP00000497574.1	P48506
GCLC	ENST00000616923.5	TSL:1	c.1544-8G>A	splice_region intron	N/A	ENSP00000482756.2	B4E2I4
GCLC	ENST00000515580.1	TSL:1	n.1307-8G>A	splice_region intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

150052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000662

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00110

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000813

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000531

AC:

131

AN:

246888

AF XY:

0.000539

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00130

Gnomad NFE exome

AF:

0.000891

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.000596

AC:

860

AN:

1442506

Hom.:

Cov.:

AF XY:

0.000600

AC XY:

431

AN XY:

718602

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

33052

American (AMR)

AF:

0.00

AC:

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25948

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39588

South Asian (SAS)

AF:

0.00

AC:

AN:

85610

European-Finnish (FIN)

AF:

0.00148

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.000688

AC:

753

AN:

1094904

Other (OTH)

AF:

0.000369

AC:

AN:

59674

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

127

169

211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

112

140

<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:

0.000446

AC:

AN:

150146

Hom.:

Cov.:

AF XY:

0.000410

AC XY:

AN XY:

73132

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40750

American (AMR)

AF:

0.0000661

AC:

AN:

15126

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4732

European-Finnish (FIN)

AF:

0.00110

AC:

AN:

9980

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000813

AC:

AN:

67658

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.000595

Hom.:

Bravo

AF:

0.000302

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.98

(source)

DANN

Benign

0.27

PhyloP100

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00025

dbscSNV1_RF

Benign

0.024

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