dbSNP rs661603: GCLC:c.1395+83A>G (chr6-53505309-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001498.4(GCLC):c.1395+83A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 727,974 control chromosomes in the GnomAD database, including 90,284 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.53 ( 22331 hom., cov: 31)

Exomes 𝑓: 0.48 ( 67953 hom. )

Consequence

GCLC
NM_001498.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.332

Publications

13 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 6-53505309-T-C is Benign according to our data. Variant chr6-53505309-T-C is described in ClinVar as Benign. ClinVar VariationId is 1289924.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.678 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.1395+83A>G	intron	N/A	NP_001489.1	P48506
GCLC	NM_001197115.2		c.1281+83A>G	intron	N/A	NP_001184044.1	E1CEI4
GCLC-AS1	NR_183318.1		n.327-845T>C	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GCLC	ENST00000650454.1	MANE Select	c.1395+83A>G	intron	N/A	ENSP00000497574.1	P48506
GCLC	ENST00000616923.5	TSL:1	c.1236+83A>G	intron	N/A	ENSP00000482756.2	B4E2I4
GCLC	ENST00000643939.1		c.1401+83A>G	intron	N/A	ENSP00000495686.1	A0A2R8YEL6

Frequencies

GnomAD3 genomes

AF:

0.528

AC:

80094

AN:

151684

Hom.:

22297

Cov.:

show subpopulations

Gnomad AFR

AF:

0.685

Gnomad AMI

AF:

0.400

Gnomad AMR

AF:

0.605

Gnomad ASJ

AF:

0.400

Gnomad EAS

AF:

0.593

Gnomad SAS

AF:

0.530

Gnomad FIN

AF:

0.473

Gnomad MID

AF:

0.506

Gnomad NFE

AF:

0.428

Gnomad OTH

AF:

0.501

GnomAD2 exomes

AF:

0.513

AC:

76977

AN:

150098

AF XY:

0.504

show subpopulations

Gnomad AFR exome

AF:

0.689

Gnomad AMR exome

AF:

0.679

Gnomad ASJ exome

AF:

0.419

Gnomad EAS exome

AF:

0.586

Gnomad FIN exome

AF:

0.469

Gnomad NFE exome

AF:

0.431

Gnomad OTH exome

AF:

0.492

GnomAD4 exome

AF:

0.477

AC:

274928

AN:

576168

Hom.:

67953

Cov.:

AF XY:

0.476

AC XY:

147647

AN XY:

310046

show subpopulations

African (AFR)

AF:

0.686

AC:

10776

AN:

15718

American (AMR)

AF:

0.668

AC:

22570

AN:

33786

Ashkenazi Jewish (ASJ)

AF:

0.417

AC:

8225

AN:

19744

East Asian (EAS)

AF:

0.637

AC:

20362

AN:

31972

South Asian (SAS)

AF:

0.520

AC:

31597

AN:

60810

European-Finnish (FIN)

AF:

0.467

AC:

22384

AN:

47916

Middle Eastern (MID)

AF:

0.517

AC:

1924

AN:

3718

European-Non Finnish (NFE)

AF:

0.429

AC:

142221

AN:

331686

Other (OTH)

AF:

0.482

AC:

14869

AN:

30818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

7150

14301

21451

28602

35752

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1102

2204

3306

4408

5510

<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:

0.528

AC:

80194

AN:

151806

Hom.:

22331

Cov.:

AF XY:

0.533

AC XY:

39516

AN XY:

74198

show subpopulations

African (AFR)

AF:

0.685

AC:

28332

AN:

41378

American (AMR)

AF:

0.605

AC:

9220

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.400

AC:

1387

AN:

3466

East Asian (EAS)

AF:

0.594

AC:

3059

AN:

5150

South Asian (SAS)

AF:

0.530

AC:

2555

AN:

4818

European-Finnish (FIN)

AF:

0.473

AC:

4974

AN:

10518

Middle Eastern (MID)

AF:

0.507

AC:

149

AN:

294

European-Non Finnish (NFE)

AF:

0.428

AC:

29096

AN:

67934

Other (OTH)

AF:

0.505

AC:

1058

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1800

3599

5399

7198

8998

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

690

1380

2070

2760

3450

<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:

0.467

Hom.:

4836

Bravo

AF:

0.546

Asia WGS

AF:

0.558

AC:

1938

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

4.4

(source)

DANN

Benign

0.53

PhyloP100

-0.33

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)

0.0

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