chr6-53536789-T-C

Variant names:

• chr6-53536789-T-C
• rs2397147
• NM_001498.4:c.150+7707A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001498.4(GCLC):​c.150+7707A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 152,120 control chromosomes in the GnomAD database, including 8,333 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.32 (8333 hom., cov: 33)
• Consequence: GCLC NM_001498.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.71
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCLC	NM_001498.4	c.150+7707A>G		intron_variant	Intron 1 of 15	ENST00000650454.1	NP_001489.1
GCLC	NM_001197115.2	c.150+7707A>G		intron_variant	Intron 1 of 14		NP_001184044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCLC	ENST00000650454.1	c.150+7707A>G		intron_variant	Intron 1 of 15		NM_001498.4	ENSP00000497574.1

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48631 AN: 152002 Hom.: 8336 Cov.: 33

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.346

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.392

Gnomad OTH AF: 0.320

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.320 AC: 48625 AN: 152120 Hom.: 8333 Cov.: 33 AF XY: 0.318 AC XY: 23640 AN XY: 74360

African (AFR) AF: 0.225 AC: 9358 AN: 41508

American (AMR) AF: 0.244 AC: 3736 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 1121 AN: 3464

East Asian (EAS) AF: 0.169 AC: 878 AN: 5184

South Asian (SAS) AF: 0.307 AC: 1478 AN: 4822

European-Finnish (FIN) AF: 0.409 AC: 4315 AN: 10544

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.392 AC: 26659 AN: 67986

Other (OTH) AF: 0.319 AC: 675 AN: 2114

Alfa AF: 0.365 Hom.: 39786

Bravo AF: 0.303

Asia WGS AF: 0.241 AC: 840 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.10
DANN	Benign	0.67
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2397147; hg19: chr6-53401587;