6-53498879-C-T

Position:

• chr6-53498879-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001498.4(GCLC):​c.1791G>A​(p.Met597Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GCLC NM_001498.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.325

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06588325).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCLC	NM_001498.4	c.1791G>A	p.Met597Ile	missense_variant	16/16	ENST00000650454.1	NP_001489.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCLC	ENST00000650454.1	c.1791G>A	p.Met597Ile	missense_variant	16/16		NM_001498.4	ENSP00000497574.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2024

GCLC: PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	8.8
DANN	Benign	0.74
DEOGEN2	Benign	0.23	.;T;T;T;.;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.89	D;.;D;D;D;D
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.066	T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-2.3	.;N;N;.;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	2.2	.;.;N;.;.;.
REVEL	Benign	0.21
Sift	Benign	1.0	.;.;T;.;.;.
Sift4G	Benign	1.0	.;.;T;.;.;.
Polyphen		0.0	.;B;B;.;.;.
Vest4		0.098
MutPred		0.60		.;Loss of disorder (P = 0.1787);Loss of disorder (P = 0.1787);.;.;.;
MVP		0.47
MPC		0.67
ClinPred		0.17	T
GERP RS		1.6
Varity_R		0.047
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-53363677; COSMIC: COSV57597158; COSMIC: COSV57597158;