rs2066509

Positions:

chr6-53500265-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_001498.4(GCLC):c.1563C>T(p.Asp521=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00525 in 1,613,908 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0054 ( 34 hom. )

Consequence

GCLC
NM_001498.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.78

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:):

GCLC-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 6-53500265-G-A is Benign according to our data. Variant chr6-53500265-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 708373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCLC	NM_001498.4 linkuse as main transcript	c.1563C>T	p.Asp521=	synonymous_variant	14/16	ENST00000650454.1
GCLC-AS1	NR_183318.1 linkuse as main transcript	n.327-5889G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCLC	ENST00000650454.1 linkuse as main transcript	c.1563C>T	p.Asp521=	synonymous_variant	14/16		NM_001498.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00347

AC:

528

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00660

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00342

AC:

858

AN:

250698

Hom.:

AF XY:

0.00337

AC XY:

456

AN XY:

135460

show subpopulations

Gnomad AFR exome

AF:

0.000862

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.000796

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.00282

Gnomad NFE exome

AF:

0.00641

Gnomad OTH exome

AF:

0.00311

GnomAD4 exome

AF:

0.00543

AC:

7938

AN:

1461592

Hom.:

Cov.:

AF XY:

0.00527

AC XY:

3835

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.000671

Gnomad4 ASJ exome

AF:

0.000689

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000533

Gnomad4 FIN exome

AF:

0.00245

Gnomad4 NFE exome

AF:

0.00671

Gnomad4 OTH exome

AF:

0.00371

GnomAD4 genome

AF:

0.00347

AC:

528

AN:

152316

Hom.:

Cov.:

AF XY:

0.00325

AC XY:

242

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00120

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00660

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00560

Hom.:

Bravo

AF:

0.00308

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00676

EpiControl

AF:

0.00533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	GCLC: BP4, BP7, BS2 -

GCLC-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2019

This variant is classified as likely 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

-0.43

CADD

Benign

7.9

DANN

Benign

0.82

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over