Genetic Variant GCLC:c.446+101G>A (chr6-53520677-C-T) – 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.446+101G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 917,964 control chromosomes in the GnomAD database, including 44,765 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.28 ( 6536 hom., cov: 32)

Exomes 𝑓: 0.31 ( 38229 hom. )

Consequence

GCLC
NM_001498.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.449

Publications

11 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=-0.91).

BP6

Variant 6-53520677-C-T is Benign according to our data. Variant chr6-53520677-C-T is described in ClinVar as Benign. ClinVar VariationId is 1241264.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.417 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLC	NM_001498.4	MANE Select	c.446+101G>A		intron	N/A	NP_001489.1	P48506
	GCLC	NM_001197115.2		c.446+101G>A		intron	N/A	NP_001184044.1	E1CEI4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GCLC	ENST00000650454.1	MANE Select	c.446+101G>A	intron	N/A	ENSP00000497574.1	P48506
GCLC	ENST00000616923.5	TSL:1	c.287+101G>A	intron	N/A	ENSP00000482756.2	B4E2I4
GCLC	ENST00000514004.5	TSL:1	c.446+101G>A	intron	N/A	ENSP00000421908.1	A0A0C4DGB2

Frequencies

GnomAD3 genomes

AF:

0.284

AC:

43168

AN:

151984

Hom.:

6517

Cov.:

show subpopulations

Gnomad AFR

AF:

0.221

Gnomad AMI

AF:

0.272

Gnomad AMR

AF:

0.425

Gnomad ASJ

AF:

0.236

Gnomad EAS

AF:

0.384

Gnomad SAS

AF:

0.347

Gnomad FIN

AF:

0.280

Gnomad MID

AF:

0.266

Gnomad NFE

AF:

0.282

Gnomad OTH

AF:

0.278

GnomAD4 exome

AF:

0.306

AC:

234195

AN:

765862

Hom.:

38229

AF XY:

0.305

AC XY:

124899

AN XY:

408940

show subpopulations

African (AFR)

AF:

0.213

AC:

4307

AN:

20266

American (AMR)

AF:

0.527

AC:

23087

AN:

43804

Ashkenazi Jewish (ASJ)

AF:

0.247

AC:

5373

AN:

21794

East Asian (EAS)

AF:

0.420

AC:

15371

AN:

36612

South Asian (SAS)

AF:

0.338

AC:

24302

AN:

71802

European-Finnish (FIN)

AF:

0.281

AC:

13519

AN:

48178

Middle Eastern (MID)

AF:

0.294

AC:

1227

AN:

4176

European-Non Finnish (NFE)

AF:

0.283

AC:

136070

AN:

481630

Other (OTH)

AF:

0.291

AC:

10939

AN:

37600

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

8846

17691

26537

35382

44228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2502

5004

7506

10008

12510

<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:

0.284

AC:

43215

AN:

152102

Hom.:

6536

Cov.:

AF XY:

0.288

AC XY:

21429

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.221

AC:

9180

AN:

41492

American (AMR)

AF:

0.426

AC:

6503

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.236

AC:

819

AN:

3464

East Asian (EAS)

AF:

0.385

AC:

1991

AN:

5174

South Asian (SAS)

AF:

0.348

AC:

1679

AN:

4822

European-Finnish (FIN)

AF:

0.280

AC:

2961

AN:

10568

Middle Eastern (MID)

AF:

0.262

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.282

AC:

19156

AN:

67978

Other (OTH)

AF:

0.284

AC:

601

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1589

3179

4768

6358

7947

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

446

892

1338

1784

2230

<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:

0.293

Hom.:

9929

Bravo

AF:

0.294

Asia WGS

AF:

0.340

AC:

1183

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

-0.91

CADD

Benign

0.17

(source)

DANN

Benign

0.62

PhyloP100

-0.45

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