6-53498978-G-C

Variant names:

• chr6-53498978-G-C
• rs2066507
• NM_001498.4:c.1703-11C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001498.4(GCLC):​c.1703-11C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,581,032 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (97 hom.)
• Consequence: GCLC NM_001498.4 intron
• Scores: Splicing: ADA: 0.0002752
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.02
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 6-53498978-G-C is Benign according to our data. Variant chr6-53498978-G-C is described in ClinVar as Benign. ClinVar VariationId is 811041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0586 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.1703-11C>G		intron	N/A	NP_001489.1	P48506
	GCLC	NM_001197115.2		c.1589-11C>G		intron	N/A	NP_001184044.1	E1CEI4
	GCLC-AS1	NR_183318.1		n.327-7176G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLC	ENST00000650454.1	MANE Select	c.1703-11C>G		intron	N/A	ENSP00000497574.1	P48506
	GCLC	ENST00000616923.5	TSL:1	c.1544-11C>G		intron	N/A	ENSP00000482756.2	B4E2I4
	GCLC	ENST00000515580.1	TSL:1	n.1307-11C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00272 AC: 411 AN: 151226 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.000535

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.0641

Gnomad SAS AF: 0.00209

Gnomad FIN AF: 0.0000972

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000295

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00603 AC: 1478 AN: 245266 AF XY: 0.00554

Gnomad AFR exome AF: 0.000868

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.000807

Gnomad EAS exome AF: 0.0741

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.00183

GnomAD4 exome AF: 0.00230 AC: 3292 AN: 1429688 Hom.: 97 Cov.: 27 AF XY: 0.00226 AC XY: 1613 AN XY: 712754

African (AFR) AF: 0.000367 AC: 12 AN: 32724

American (AMR) AF: 0.000225 AC: 10 AN: 44414

Ashkenazi Jewish (ASJ) AF: 0.000775 AC: 20 AN: 25816

East Asian (EAS) AF: 0.0638 AC: 2523 AN: 39530

South Asian (SAS) AF: 0.00191 AC: 162 AN: 85036

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53306

Middle Eastern (MID) AF: 0.000528 AC: 3 AN: 5686

European-Non Finnish (NFE) AF: 0.000237 AC: 257 AN: 1083958

Other (OTH) AF: 0.00483 AC: 286 AN: 59218

GnomAD4 genome AF: 0.00272 AC: 411 AN: 151344 Hom.: 10 Cov.: 32 AF XY: 0.00286 AC XY: 211 AN XY: 73888

African (AFR) AF: 0.000533 AC: 22 AN: 41264

American (AMR) AF: 0.00105 AC: 16 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.0643 AC: 333 AN: 5180

South Asian (SAS) AF: 0.00209 AC: 10 AN: 4784

European-Finnish (FIN) AF: 0.0000972 AC: 1 AN: 10286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000295 AC: 20 AN: 67818

Other (OTH) AF: 0.00380 AC: 8 AN: 2104

Alfa AF: 0.000898 Hom.: 2

Bravo AF: 0.00321

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.021
DANN	Benign	0.32
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.040
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: rs2066507; hg19: chr6-53363776;