NR3C1 p.Arg23Lys

Variant names:

• chr5-143400772-C-T
• rs6190
• NM_000176.3:c.68G>A
• NR3C1 p.Arg23Lys

Your query was ambiguous. Multiple possible variants found:

• chr5-143400772-C-T
• chr5-143400771-CC-TT

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-5 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -5 classification points (ACGS-UK Somatic Oncogenicity v2025). B1_StrongB3_Supporting

The NM_000176.3(NR3C1):c.68G>A (p.Arg23Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene NR3C1 is a tumor suppressor gene (CancerMine: 5 TSG, 2 oncogene, 1 driver citations). The gene NR3C1 is a known oncogene (CancerMine: 5 TSG, 2 oncogene, 1 driver citations). The gene NR3C1 is a cancer driver gene (CancerMine: 5 TSG, 2 oncogene, 1 driver citations). The variant allele was found at a cumulative frequency of 0.024 (AC=38,732) in the gnomAD database across 1,614,144 control chromosomes, including 590 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.028. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R23K: Uncertain_significance (ClinVar VariationId 1333751, 1 star) The variant has been observed in cBioPortal in 1 sample across 1 study and 1 cancer type; somatic enrichment level: NONE (Observed in at most one deduplicated cBioPortal case.). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.017 (42 hom., cov: 32)
  • Exomes 𝑓: 0.025 (548 hom.)
• Consequence: NR3C1 NM_000176.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.77
• Publications: 46 publications found

Genes affected

NR3C1 (HGNC:7978): (nuclear receptor subfamily 3 group C member 1) This gene encodes glucocorticoid receptor, which can function both as a transcription factor that binds to glucocorticoid response elements in the promoters of glucocorticoid responsive genes to activate their transcription, and as a regulator of other transcription factors. This receptor is typically found in the cytoplasm, but upon ligand binding, is transported into the nucleus. It is involved in inflammatory responses, cellular proliferation, and differentiation in target tissues. Mutations in this gene are associated with generalized glucocorticoid resistance. Alternative splicing of this gene results in transcript variants encoding either the same or different isoforms. Additional isoforms resulting from the use of alternate in-frame translation initiation sites have also been described, and shown to be functional, displaying diverse cytoplasm-to-nucleus trafficking patterns and distinct transcriptional activities (PMID:15866175). [provided by RefSeq, Feb 2011]

NR3C1 Gene-Disease associations (from GenCC):

• glucocorticoid resistance

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet, Ambry Genetics

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	B1High frequency in general population		GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.028 — exceeds 1% threshold (B1 applied)
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000176.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NR3C1 NM_000176.3	MANE Select	c.68G>A p.Arg23Lys	missense	Exon 2 of 9	Prot: NP_000167.1 UniProt:
	NR3C1 NM_001024094.2		c.68G>A p.Arg23Lys	missense	Exon 2 of 9	Prot: NP_001019265.1 UniProt:
	NR3C1 NM_001364183.2		c.68G>A p.Arg23Lys	missense	Exon 3 of 10	Prot: NP_001351112.1 UniProt:

NR3C1 NM_000176.3

MANE Select

HGVSc / HGVSpc.68G>Ap.Arg23Lys

Exon rankExon 2 of 9

missense

Prot: NP_000167.1UniProt: F1D8N4P04150-1

NR3C1 NM_001024094.2

HGVSc / HGVSpc.68G>Ap.Arg23Lys

Exon rankExon 2 of 9

missense

Prot: NP_001019265.1UniProt: E5KQF6P04150-3

NR3C1 NM_001364183.2

HGVSc / HGVSpc.68G>Ap.Arg23Lys

Exon rankExon 3 of 10

missense

Prot: NP_001351112.1UniProt: E5KQF6P04150-3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NR3C1 ENST00000394464.7	TSL:1MANE Select	c.68G>A p.Arg23Lys	missense	Exon 2 of 9	Prot: ENSP00000377977.2 UniProt:
	NR3C1 ENST00000231509.7	TSL:1	c.68G>A p.Arg23Lys	missense	Exon 2 of 9	Prot: ENSP00000231509.3 UniProt:
	NR3C1 ENST00000504572.5	TSL:1	c.68G>A p.Arg23Lys	missense	Exon 3 of 10	Prot: ENSP00000422518.1 UniProt:

NR3C1 ENST00000394464.7

TSL:1MANE Select

HGVSc / HGVSpc.68G>Ap.Arg23Lys

Exon rankExon 2 of 9

missense

Prot: ENSP00000377977.2UniProt: P04150-1

NR3C1 ENST00000231509.7

TSL:1

HGVSc / HGVSpc.68G>Ap.Arg23Lys

Exon rankExon 2 of 9

missense

Prot: ENSP00000231509.3UniProt: P04150-3

NR3C1 ENST00000504572.5

TSL:1

HGVSc / HGVSpc.68G>Ap.Arg23Lys

Exon rankExon 3 of 10

missense

Prot: ENSP00000422518.1UniProt: P04150-3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0166	AC:2533	Hom:42	AN:152194	Cov:32
GnomAD2 exomes	AF: 0.0183	AC:4603	Hom:	AN:251468	Cov:
GnomAD4 exome	AF: 0.0248	AC:36197	Hom:548	AN:1461832	Cov:32
GnomAD4 genome	AF: 0.0166	AC:2535	Hom:42	AN:152312	Cov:32
TOPMed (Bravo)	AF: 0.0149	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0222	AC:15685	Hom:222	AN:707330	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0132	AC:31	Hom:1	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.000197	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.0233	AC:7	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0203	AC:264	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.00751	AC:26	Hom:	AN:3478	Cov:
Qatari Genome	AF: 0.0100	AC:17	Hom:	AN:1706	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000240	AC:3	Hom:0	AN:122764	Cov:
Turkish Variome	AF: 0.0214	AC:143	Hom:0	AN:6684	Cov:
UK10K	AF: 0.0287	AC:217	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000335	AC:3	Hom:0	AN:8960	Cov:

Showing 16 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.0272 *	302	11110	0.0280 *	493	17614
BipEx(Bipolar disorder (including schizoaffective))	0.0271	770	28420	0.0265	764	28844
Epi25(Epilepsy)	0.0212	890	41958	0.0231	1544	66888
SCHEMA(Schizophrenia)	0.0176	2153	122096	0.0204	3899	191438

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Glucocorticoid resistance (1)
-	-	1	NR3C1-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	14
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.044
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.93	D
GPN-Star LLR	N/A	-2.6
GPN-Star score	N/A	2.6
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.54	T
Mutation Taster	N/A	99/1	polymorphism (auto)
MutationAssessor	Benign	1.8	L
PhyloP100	Uncertain	3.8
popEVE	Benign	-3.2
PrimateAI	Benign	0.36	T
PromoterAI	N/A	0.014	Neutral
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.14
Sift	Benign	0.035	D
Sift4G	Benign	0.98	T
Varity_R	N/A	0.18
VESM-3B	Benign	-2.1

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs6190;

hg19: chr5-142780337;

COSMIC: COSV99039780;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar