Genetic Variant GCLC:c.1291-101G>A (chr6-53505597-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.1291-101G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 771,814 control chromosomes in the GnomAD database, including 17,954 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.20 ( 3053 hom., cov: 31)

Exomes 𝑓: 0.21 ( 14901 hom. )

Consequence

GCLC
NM_001498.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.283

Publications

14 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=-0.82).

BP6

Variant 6-53505597-C-T is Benign according to our data. Variant chr6-53505597-C-T is described in ClinVar as Benign. ClinVar VariationId is 1235148.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.239 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.1291-101G>A	intron	N/A	NP_001489.1	P48506
GCLC	NM_001197115.2		c.1177-101G>A	intron	N/A	NP_001184044.1	E1CEI4
GCLC-AS1	NR_183318.1		n.327-557C>T	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GCLC	ENST00000650454.1	MANE Select	c.1291-101G>A	intron	N/A	ENSP00000497574.1	P48506
GCLC	ENST00000616923.5	TSL:1	c.1132-101G>A	intron	N/A	ENSP00000482756.2	B4E2I4
GCLC	ENST00000643939.1		c.1297-101G>A	intron	N/A	ENSP00000495686.1	A0A2R8YEL6

Frequencies

GnomAD3 genomes

AF:

0.195

AC:

29691

AN:

151906

Hom.:

3053

Cov.:

show subpopulations

Gnomad AFR

AF:

0.146

Gnomad AMI

AF:

0.164

Gnomad AMR

AF:

0.143

Gnomad ASJ

AF:

0.185

Gnomad EAS

AF:

0.132

Gnomad SAS

AF:

0.133

Gnomad FIN

AF:

0.232

Gnomad MID

AF:

0.173

Gnomad NFE

AF:

0.242

Gnomad OTH

AF:

0.189

GnomAD4 exome

AF:

0.214

AC:

132420

AN:

619790

Hom.:

14901

Cov.:

AF XY:

0.211

AC XY:

70441

AN XY:

333058

show subpopulations

African (AFR)

AF:

0.139

AC:

2315

AN:

16638

American (AMR)

AF:

0.112

AC:

4045

AN:

35982

Ashkenazi Jewish (ASJ)

AF:

0.186

AC:

3802

AN:

20460

East Asian (EAS)

AF:

0.168

AC:

5457

AN:

32546

South Asian (SAS)

AF:

0.143

AC:

9226

AN:

64602

European-Finnish (FIN)

AF:

0.232

AC:

11486

AN:

49502

Middle Eastern (MID)

AF:

0.191

AC:

786

AN:

4120

European-Non Finnish (NFE)

AF:

0.244

AC:

88637

AN:

363444

Other (OTH)

AF:

0.205

AC:

6666

AN:

32496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

6202

12404

18607

24809

31011

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

844

1688

2532

3376

4220

<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:

0.195

AC:

29690

AN:

152024

Hom.:

3053

Cov.:

AF XY:

0.192

AC XY:

14275

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.146

AC:

6051

AN:

41468

American (AMR)

AF:

0.143

AC:

2184

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.185

AC:

643

AN:

3468

East Asian (EAS)

AF:

0.133

AC:

684

AN:

5162

South Asian (SAS)

AF:

0.132

AC:

639

AN:

4824

European-Finnish (FIN)

AF:

0.232

AC:

2440

AN:

10512

Middle Eastern (MID)

AF:

0.172

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.242

AC:

16447

AN:

67996

Other (OTH)

AF:

0.190

AC:

402

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1227

2453

3680

4906

6133

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

326

652

978

1304

1630

<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:

0.224

Hom.:

15013

Bravo

AF:

0.187

Asia WGS

AF:

0.130

AC:

452

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

-0.82

CADD

Benign

6.3

(source)

DANN

Benign

0.55

PhyloP100

-0.28

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