6-53499767-C-T

Variant names:

• chr6-53499767-C-T
• rs12524550
• NM_001498.4:c.1702+278G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001498.4(GCLC):​c.1702+278G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0309 in 152,060 control chromosomes in the GnomAD database, including 87 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 0.031 (87 hom., cov: 32)
• Consequence: GCLC NM_001498.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.165
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0309 (4698/152060) while in subpopulation AFR AF = 0.0503 (2085/41490). AF 95% confidence interval is 0.0485. There are 87 homozygotes in GnomAd4. There are 2308 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 87 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCLC	NM_001498.4	c.1702+278G>A		intron_variant	Intron 15 of 15	ENST00000650454.1	NP_001489.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCLC	ENST00000650454.1	c.1702+278G>A		intron_variant	Intron 15 of 15		NM_001498.4	ENSP00000497574.1

Frequencies

GnomAD3 genomes AF: 0.0308 AC: 4685 AN: 151942 Hom.: 83 Cov.: 32

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0284

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0202

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0250

Gnomad OTH AF: 0.0364

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

GnomAD4 genome AF: 0.0309 AC: 4698 AN: 152060 Hom.: 87 Cov.: 32 AF XY: 0.0311 AC XY: 2308 AN XY: 74328

African (AFR) AF: 0.0503 AC: 2085 AN: 41490

American (AMR) AF: 0.0284 AC: 433 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0280 AC: 97 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4816

European-Finnish (FIN) AF: 0.0202 AC: 213 AN: 10554

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0250 AC: 1698 AN: 67986

Other (OTH) AF: 0.0361 AC: 76 AN: 2108

Alfa AF: 0.0239 Hom.: 68

Bravo AF: 0.0320

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.9
DANN	Benign	0.34
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism

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: rs12524550; hg19: chr6-53364565;