6-53498806-C-A

Position:

• chr6-53498806-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001498.4(GCLC):​c.1864G>T​(p.Ala622Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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: 3.71

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-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1347605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCLC	NM_001498.4	c.1864G>T	p.Ala622Ser	missense_variant	16/16	ENST00000650454.1	NP_001489.1
GCLC-AS1	NR_183318.1	n.327-7348C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCLC	ENST00000650454.1	c.1864G>T	p.Ala622Ser	missense_variant	16/16		NM_001498.4	ENSP00000497574	P1

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

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2022

The c.1864G>T (p.A622S) alteration is located in exon 16 (coding exon 16) of the GCLC gene. This alteration results from a G to T substitution at nucleotide position 1864, causing the alanine (A) at amino acid position 622 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.20	.;T;T;T;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T;.;T;T;T;T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.60	.;N;N;.;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.21	.;.;N;.;.;.
REVEL	Benign	0.074
Sift	Benign	0.42	.;.;T;.;.;.
Sift4G	Benign	0.43	.;.;T;.;.;.
Polyphen		0.0	.;B;B;.;.;.
Vest4		0.055
MutPred		0.29		.;Gain of disorder (P = 0.012);Gain of disorder (P = 0.012);.;.;.;
MVP		0.50
MPC		0.55
ClinPred		0.49	T
GERP RS		3.8
Varity_R		0.053
gMVP		0.34

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: chr6-53363604;