6-53545239-G-A

Variant names:

• chr6-53545239-G-A
• rs17883901
• ENST00000616923.5:c.-10+2817C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000616923.5(GCLC):​c.-10+2817C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0637 in 154,512 control chromosomes in the GnomAD database, including 344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (337 hom., cov: 32)
  • Exomes 𝑓: 0.081 (7 hom.)
• Consequence: GCLC ENST00000616923.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.743
• Publications: 62 publications found

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 Gene-Disease associations (from GenCC):

• gamma-glutamylcysteine synthetase deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 6-53545239-G-A is Benign according to our data. Variant chr6-53545239-G-A is described in ClinVar as Benign. ClinVar VariationId is 439753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCLC	NM_001498.4	c.-594C>T		upstream_gene_variant		ENST00000650454.1	NP_001489.1
GCLC	NM_001197115.2	c.-594C>T		upstream_gene_variant			NP_001184044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCLC	ENST00000650454.1	c.-594C>T		upstream_gene_variant			NM_001498.4	ENSP00000497574.1

Frequencies

GnomAD3 genomes AF: 0.0635 AC: 9664 AN: 152180 Hom.: 337 Cov.: 32

Gnomad AFR AF: 0.0254

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0545

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.0654

Gnomad FIN AF: 0.0625

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0813

Gnomad OTH AF: 0.0776

GnomAD4 exome AF: 0.0808 AC: 179 AN: 2216 Hom.: 7 AF XY: 0.0778 AC XY: 93 AN XY: 1196

African (AFR) AF: 0.0185 AC: 1 AN: 54

American (AMR) AF: 0.0313 AC: 1 AN: 32

Ashkenazi Jewish (ASJ) AF: 0.0694 AC: 5 AN: 72

East Asian (EAS) AF: 0.159 AC: 33 AN: 208

South Asian (SAS) AF: 0.0769 AC: 2 AN: 26

European-Finnish (FIN) AF: 0.0615 AC: 15 AN: 244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 8

European-Non Finnish (NFE) AF: 0.0813 AC: 117 AN: 1440

Other (OTH) AF: 0.0379 AC: 5 AN: 132

GnomAD4 genome AF: 0.0634 AC: 9662 AN: 152296 Hom.: 337 Cov.: 32 AF XY: 0.0628 AC XY: 4677 AN XY: 74466

African (AFR) AF: 0.0253 AC: 1053 AN: 41570

American (AMR) AF: 0.0545 AC: 834 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 348 AN: 3470

East Asian (EAS) AF: 0.124 AC: 641 AN: 5170

South Asian (SAS) AF: 0.0649 AC: 313 AN: 4826

European-Finnish (FIN) AF: 0.0625 AC: 663 AN: 10614

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0813 AC: 5531 AN: 68020

Other (OTH) AF: 0.0791 AC: 167 AN: 2110

Alfa AF: 0.0663 Hom.: 174

Bravo AF: 0.0622

Asia WGS AF: 0.106 AC: 369 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 10, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21962117, 12598062) -

Myocardial infarction, susceptibility to Other:1

Feb 19, 2003

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	13
DANN	Benign	0.83
PhyloP100		0.74
PromoterAI		0.080	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17883901; hg19: chr6-53410037;