Variant rs2066508 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001498.4(GCLC):c.234G>T(p.Leu78=) 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. In-silico tool predicts a benign outcome for this variant. 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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 6-53522444-C-A is Benign according to our data. Variant chr6-53522444-C-A is described in ClinVar as [Benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 88 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCLC	NM_001498.4 linkuse as main transcript	c.234G>T	p.Leu78=	synonymous_variant	2/16	ENST00000650454.1
GCLC	NM_001197115.2 linkuse as main transcript	c.234G>T	p.Leu78=	synonymous_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCLC	ENST00000650454.1 linkuse as main transcript	c.234G>T	p.Leu78=	synonymous_variant	2/16		NM_001498.4	P1

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

GnomAD3 exomes

AF:

0.0270

AC:

6789

AN:

251428

Hom.:

128

AF XY:

0.0272

AC XY:

3703

AN XY:

135896

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 SAS exome

AF:

0.0135

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

Gnomad4 AFR exome

AF:

0.00610

Gnomad4 AMR exome

AF:

0.0148

Gnomad4 ASJ exome

AF:

0.0197

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0142

Gnomad4 FIN exome

AF:

0.0462

Gnomad4 NFE exome

AF:

0.0398

Gnomad4 OTH exome

AF:

0.0280

GnomAD4 genome

AF:

0.0281

AC:

4283

AN:

152344

Hom.:

Cov.:

AF XY:

0.0276

AC XY:

2056

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00820

Gnomad4 AMR

AF:

0.0248

Gnomad4 ASJ

AF:

0.0185

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0116

Gnomad4 FIN

AF:

0.0475

Gnomad4 NFE

AF:

0.0407

Gnomad4 OTH

AF:

0.0279

Alfa

AF:

0.0361

Hom.:

122

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

GCLC-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2019

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

DANN

Benign

0.70

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