rs2066511

Variant names:

• chr6-53500576-C-T
• rs2066511
• NM_001498.4:c.1396-63G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-53500576-C-T
• chr6-53500576-C-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001498.4(GCLC):​c.1396-63G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,113,424 control chromosomes in the GnomAD database, including 36,144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (4526 hom., cov: 32)
  • Exomes 𝑓: 0.25 (31618 hom.)
• Consequence: GCLC NM_001498.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.09
• Publications: 13 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-AS1 (HGNC:56649): (GCLC antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-53500576-C-T is Benign according to our data. Variant chr6-53500576-C-T is described in ClinVar as Benign. ClinVar VariationId is 1246572.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001498.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLC	NM_001498.4	MANE Select	c.1396-63G>A		intron	N/A	NP_001489.1	P48506
	GCLC	NM_001197115.2		c.1282-63G>A		intron	N/A	NP_001184044.1	E1CEI4
	GCLC-AS1	NR_183318.1		n.327-5578C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLC	ENST00000650454.1	MANE Select	c.1396-63G>A		intron	N/A	ENSP00000497574.1	P48506
	GCLC	ENST00000616923.5	TSL:1	c.1237-63G>A		intron	N/A	ENSP00000482756.2	B4E2I4
	GCLC	ENST00000515580.1	TSL:1	n.775G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36507 AN: 151992 Hom.: 4527 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.232

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.232

GnomAD4 exome AF: 0.254 AC: 244606 AN: 961314 Hom.: 31618 Cov.: 14 AF XY: 0.252 AC XY: 125910 AN XY: 500572

African (AFR) AF: 0.233 AC: 5590 AN: 23986

American (AMR) AF: 0.132 AC: 5827 AN: 44096

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 5374 AN: 23048

East Asian (EAS) AF: 0.171 AC: 6400 AN: 37442

South Asian (SAS) AF: 0.152 AC: 11579 AN: 75986

European-Finnish (FIN) AF: 0.281 AC: 12961 AN: 46108

Middle Eastern (MID) AF: 0.235 AC: 760 AN: 3232

European-Non Finnish (NFE) AF: 0.280 AC: 185540 AN: 663748

Other (OTH) AF: 0.242 AC: 10575 AN: 43668

GnomAD4 genome AF: 0.240 AC: 36515 AN: 152110 Hom.: 4526 Cov.: 32 AF XY: 0.236 AC XY: 17559 AN XY: 74352

African (AFR) AF: 0.233 AC: 9655 AN: 41482

American (AMR) AF: 0.177 AC: 2710 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 805 AN: 3468

East Asian (EAS) AF: 0.136 AC: 703 AN: 5168

South Asian (SAS) AF: 0.141 AC: 680 AN: 4834

European-Finnish (FIN) AF: 0.275 AC: 2906 AN: 10560

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.269 AC: 18295 AN: 67992

Other (OTH) AF: 0.232 AC: 491 AN: 2116

Alfa AF: 0.256 Hom.: 8690

Bravo AF: 0.234

Asia WGS AF: 0.141 AC: 491 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.17
DANN	Benign	0.40
PhyloP100		-1.1
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: rs2066511; hg19: chr6-53365374; COSMIC: COSV57595690; COSMIC: COSV57595690;