rs2066508

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_StrongBP7BS1BS2

The NM_001498.4(GCLC):c.234G>T(p.Leu78Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0343 in 1,609,212 control chromosomes in the GnomAD database, including 1,111 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 88 hom., cov: 32)

Exomes 𝑓: 0.035 ( 1023 hom. )

Consequence

GCLC
NM_001498.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.578

Publications

8 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 -17 ACMG points.

BP6

Variant 6-53522444-C-A is Benign according to our data. Variant chr6-53522444-C-A is described in ClinVar as Benign. ClinVar VariationId is 993340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.578 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0281 (4283/152344) while in subpopulation NFE AF = 0.0407 (2768/68022). AF 95% confidence interval is 0.0394. There are 88 homozygotes in GnomAd4. There are 2056 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 88 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCLC	NM_001498.4 link	c.234G>T	p.Leu78Leu	synonymous_variant	Exon 2 of 16	ENST00000650454.1	NP_001489.1	P48506Q14TF0
GCLC	NM_001197115.2 link	c.234G>T	p.Leu78Leu	synonymous_variant	Exon 2 of 15		NP_001184044.1	P48506Q14TF0E1CEI4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCLC	ENST00000650454.1 link	c.234G>T	p.Leu78Leu	synonymous_variant	Exon 2 of 16		NM_001498.4	ENSP00000497574.1		P48506

Frequencies

GnomAD3 genomes

AF:

0.0281

AC:

4283

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00822

Gnomad AMI

AF:

0.117

Gnomad AMR

AF:

0.0249

Gnomad ASJ

AF:

0.0185

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0116

Gnomad FIN

AF:

0.0475

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0407

Gnomad OTH

AF:

0.0282

GnomAD2 exomes

AF:

0.0270

AC:

6789

AN:

251428

AF XY:

0.0272

show subpopulations

Gnomad AFR exome

AF:

0.00782

Gnomad AMR exome

AF:

0.0142

Gnomad ASJ exome

AF:

0.0164

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0455

Gnomad NFE exome

AF:

0.0389

Gnomad OTH exome

AF:

0.0303

GnomAD4 exome

AF:

0.0350

AC:

50934

AN:

1456868

Hom.:

1023

Cov.:

AF XY:

0.0346

AC XY:

25100

AN XY:

725156

show subpopulations

African (AFR)

AF:

0.00610

AC:

204

AN:

33420

American (AMR)

AF:

0.0148

AC:

660

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0197

AC:

514

AN:

26092

East Asian (EAS)

AF:

0.000126

AC:

AN:

39674

South Asian (SAS)

AF:

0.0142

AC:

1226

AN:

86164

European-Finnish (FIN)

AF:

0.0462

AC:

2465

AN:

53368

Middle Eastern (MID)

AF:

0.00937

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0398

AC:

44119

AN:

1107450

Other (OTH)

AF:

0.0280

AC:

1687

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

2317

4634

6951

9268

11585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1606

3212

4818

6424

8030

<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:

0.0281

AC:

4283

AN:

152344

Hom.:

Cov.:

AF XY:

0.0276

AC XY:

2056

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00820

AC:

341

AN:

41584

American (AMR)

AF:

0.0248

AC:

380

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0185

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.0116

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0475

AC:

505

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0407

AC:

2768

AN:

68022

Other (OTH)

AF:

0.0279

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

216

432

648

864

1080

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0345

Hom.:

180

Bravo

AF:

0.0247

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0383

EpiControl

AF:

0.0373

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GCLC-related disorder

Benign:1

Jul 08, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.53

(source)

DANN

Benign

0.70

PhyloP100

-0.58

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over