Genetic Variant GCLC:c.1703-19G>A (chr6-53498986-C-T) – 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 NM_001498.4(GCLC):c.1703-19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,534,954 control chromosomes in the GnomAD database, including 9,500 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 973 hom., cov: 31)

Exomes 𝑓: 0.11 ( 8527 hom. )

Consequence

GCLC
NM_001498.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.79

Publications

3 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 6-53498986-C-T is Benign according to our data. Variant chr6-53498986-C-T is described in ClinVar as Benign. ClinVar VariationId is 995642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

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.1703-19G>A	intron	N/A	NP_001489.1	P48506
GCLC	NM_001197115.2		c.1589-19G>A	intron	N/A	NP_001184044.1	E1CEI4
GCLC-AS1	NR_183318.1		n.327-7168C>T	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GCLC	ENST00000650454.1	MANE Select	c.1703-19G>A	intron	N/A	ENSP00000497574.1	P48506
GCLC	ENST00000616923.5	TSL:1	c.1544-19G>A	intron	N/A	ENSP00000482756.2	B4E2I4
GCLC	ENST00000515580.1	TSL:1	n.1307-19G>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.113

AC:

16788

AN:

148200

Hom.:

971

Cov.:

show subpopulations

Gnomad AFR

AF:

0.135

Gnomad AMI

AF:

0.129

Gnomad AMR

AF:

0.0849

Gnomad ASJ

AF:

0.106

Gnomad EAS

AF:

0.00862

Gnomad SAS

AF:

0.151

Gnomad FIN

AF:

0.151

Gnomad MID

AF:

0.0903

Gnomad NFE

AF:

0.107

Gnomad OTH

AF:

0.115

GnomAD2 exomes

AF:

0.107

AC:

24558

AN:

228528

AF XY:

0.112

show subpopulations

Gnomad AFR exome

AF:

0.132

Gnomad AMR exome

AF:

0.0593

Gnomad ASJ exome

AF:

0.118

Gnomad EAS exome

AF:

0.0103

Gnomad FIN exome

AF:

0.135

Gnomad NFE exome

AF:

0.110

Gnomad OTH exome

AF:

0.119

GnomAD4 exome

AF:

0.108

AC:

149715

AN:

1386642

Hom.:

8527

Cov.:

AF XY:

0.109

AC XY:

75798

AN XY:

692770

show subpopulations

African (AFR)

AF:

0.137

AC:

4250

AN:

30920

American (AMR)

AF:

0.0631

AC:

2455

AN:

38904

Ashkenazi Jewish (ASJ)

AF:

0.113

AC:

2854

AN:

25166

East Asian (EAS)

AF:

0.00562

AC:

221

AN:

39296

South Asian (SAS)

AF:

0.151

AC:

12276

AN:

81096

European-Finnish (FIN)

AF:

0.131

AC:

6985

AN:

53180

Middle Eastern (MID)

AF:

0.107

AC:

588

AN:

5514

European-Non Finnish (NFE)

AF:

0.108

AC:

113801

AN:

1054998

Other (OTH)

AF:

0.109

AC:

6285

AN:

57568

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

6898

13797

20695

27594

34492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4174

8348

12522

16696

20870

<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:

0.113

AC:

16790

AN:

148312

Hom.:

973

Cov.:

AF XY:

0.114

AC XY:

8225

AN XY:

72142

show subpopulations

African (AFR)

AF:

0.134

AC:

5412

AN:

40316

American (AMR)

AF:

0.0847

AC:

1267

AN:

14964

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

365

AN:

3446

East Asian (EAS)

AF:

0.00864

AC:

AN:

5092

South Asian (SAS)

AF:

0.150

AC:

709

AN:

4728

European-Finnish (FIN)

AF:

0.151

AC:

1441

AN:

9520

Middle Eastern (MID)

AF:

0.0972

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.107

AC:

7172

AN:

67000

Other (OTH)

AF:

0.114

AC:

236

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

761

1522

2283

3044

3805

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

368

552

736

920

<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:

0.107

Hom.:

174

Bravo

AF:

0.106

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.3

(source)

DANN

Benign

0.57

PhyloP100

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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