rs2064764

Positions:

• chr1-93892787-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002061.4(GCLM):​c.655+1827G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 151,980 control chromosomes in the GnomAD database, including 16,898 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 0.44 (16898 hom., cov: 32)
• Consequence: GCLM NM_002061.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.80

Genes affected

GCLM (HGNC:4312): (glutamate-cysteine ligase modifier 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. Gamma glutamylcysteine synthetase deficiency has been implicated in some forms of hemolytic anemia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCLM	NM_002061.4	c.655+1827G>A		intron_variant		ENST00000370238.8	NP_002052.1
GCLM	NM_001308253.2	c.589+1827G>A		intron_variant			NP_001295182.1
GCLM	XM_011541261.3	c.391+1827G>A		intron_variant			XP_011539563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCLM	ENST00000370238.8	c.655+1827G>A		intron_variant		1	NM_002061.4	ENSP00000359258.3
GCLM	ENST00000615724.1	c.589+1827G>A		intron_variant		1		ENSP00000484507.1

Frequencies

GnomAD3 genomes AF: 0.445 AC: 67506 AN: 151860 Hom.: 16863 Cov.: 32

Gnomad AFR AF: 0.681

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.334

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.416

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

GnomAD4 genome AF: 0.445 AC: 67597 AN: 151980 Hom.: 16898 Cov.: 32 AF XY: 0.442 AC XY: 32850 AN XY: 74308

Gnomad4 AFR AF: 0.681

Gnomad4 AMR AF: 0.463

Gnomad4 ASJ AF: 0.302

Gnomad4 EAS AF: 0.222

Gnomad4 SAS AF: 0.225

Gnomad4 FIN AF: 0.351

Gnomad4 NFE AF: 0.354

Gnomad4 OTH AF: 0.416

Alfa AF: 0.413 Hom.: 1753

Bravo AF: 0.467

Asia WGS AF: 0.247 AC: 860 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.091
DANN	Benign	0.62

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

LitVar

Other links and lift over

dbSNP: rs2064764; hg19: chr1-94358343;