6-53520677-C-T

Variant names:

• chr6-53520677-C-T
• rs2100375
• NM_001498.4:c.446+101G>A

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.446+101G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 917,964 control chromosomes in the GnomAD database, including 44,765 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (6536 hom., cov: 32)
  • Exomes 𝑓: 0.31 (38229 hom.)
• Consequence: GCLC NM_001498.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.449
• Publications: 11 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=-0.91).
• BP6: Variant 6-53520677-C-T is Benign according to our data. Variant chr6-53520677-C-T is described in ClinVar as Benign. ClinVar VariationId is 1241264.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.417 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.446+101G>A		intron	N/A	NP_001489.1
	GCLC	NM_001197115.2		c.446+101G>A		intron	N/A	NP_001184044.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLC	ENST00000650454.1	MANE Select	c.446+101G>A		intron	N/A	ENSP00000497574.1
	GCLC	ENST00000616923.5	TSL:1	c.287+101G>A		intron	N/A	ENSP00000482756.2
	GCLC	ENST00000514004.5	TSL:1	c.446+101G>A		intron	N/A	ENSP00000421908.1

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43168 AN: 151984 Hom.: 6517 Cov.: 32

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.425

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.278

GnomAD4 exome AF: 0.306 AC: 234195 AN: 765862 Hom.: 38229 AF XY: 0.305 AC XY: 124899 AN XY: 408940

African (AFR) AF: 0.213 AC: 4307 AN: 20266

American (AMR) AF: 0.527 AC: 23087 AN: 43804

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 5373 AN: 21794

East Asian (EAS) AF: 0.420 AC: 15371 AN: 36612

South Asian (SAS) AF: 0.338 AC: 24302 AN: 71802

European-Finnish (FIN) AF: 0.281 AC: 13519 AN: 48178

Middle Eastern (MID) AF: 0.294 AC: 1227 AN: 4176

European-Non Finnish (NFE) AF: 0.283 AC: 136070 AN: 481630

Other (OTH) AF: 0.291 AC: 10939 AN: 37600

GnomAD4 genome AF: 0.284 AC: 43215 AN: 152102 Hom.: 6536 Cov.: 32 AF XY: 0.288 AC XY: 21429 AN XY: 74342

African (AFR) AF: 0.221 AC: 9180 AN: 41492

American (AMR) AF: 0.426 AC: 6503 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 819 AN: 3464

East Asian (EAS) AF: 0.385 AC: 1991 AN: 5174

South Asian (SAS) AF: 0.348 AC: 1679 AN: 4822

European-Finnish (FIN) AF: 0.280 AC: 2961 AN: 10568

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.282 AC: 19156 AN: 67978

Other (OTH) AF: 0.284 AC: 601 AN: 2116

Alfa AF: 0.293 Hom.: 9929

Bravo AF: 0.294

Asia WGS AF: 0.340 AC: 1183 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.91
CADD	Benign	0.17
DANN	Benign	0.62
PhyloP100		-0.45
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: rs2100375; hg19: chr6-53385475; COSMIC: COSV57594145; COSMIC: COSV57594145;