5-143400774-C-T

Variant names:

• chr5-143400774-C-T
• rs6189
• NM_000176.3:c.66G>A
• NR3C1 p.Glu22Glu

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -17 classification points (ACMG Germline Pathogenicity v2019). BS1BS2BP4_StrongBP6_StrongBP7

The NM_000176.3(NR3C1):c.66G>A (p.Glu22Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.024 (AC=38,735) in the gnomAD database across 1,614,150 control chromosomes, including 590 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.028. In-silico predictor (BayesDel (noAF)) 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (42 hom., cov: 32)
  • Exomes 𝑓: 0.025 (548 hom.)
• Consequence: NR3C1 NM_000176.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.387
• Publications: 140 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -17 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).
	BS1Allele frequency higher than expected		GnomAD effective popmax AF above BS1 threshold — greater than expected for disorder; GnomAD effective popmax AF = 0.028 vs gene BS1 threshold 0.015.
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 590.; Very high cumulative gnomAD AC = 38735 (any gene).

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.66G>A p.Glu22Glu	synonymous	Exon 2 of 9	Prot: NP_000167.1 UniProt:
	NR3C1 NM_001024094.2		c.66G>A p.Glu22Glu	synonymous	Exon 2 of 9	Prot: NP_001019265.1 UniProt:
	NR3C1 NM_001364183.2		c.66G>A p.Glu22Glu	synonymous	Exon 3 of 10	Prot: NP_001351112.1 UniProt:

NR3C1 NM_000176.3

MANE Select

HGVSc / HGVSpc.66G>Ap.Glu22Glu

Exon rankExon 2 of 9

synonymous

Prot: NP_000167.1UniProt: F1D8N4P04150-1

NR3C1 NM_001024094.2

HGVSc / HGVSpc.66G>Ap.Glu22Glu

Exon rankExon 2 of 9

synonymous

Prot: NP_001019265.1UniProt: E5KQF6P04150-3

NR3C1 NM_001364183.2

HGVSc / HGVSpc.66G>Ap.Glu22Glu

Exon rankExon 3 of 10

synonymous

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.66G>A p.Glu22Glu	synonymous	Exon 2 of 9	Prot: ENSP00000377977.2 UniProt:
	NR3C1 ENST00000231509.7	TSL:1	c.66G>A p.Glu22Glu	synonymous	Exon 2 of 9	Prot: ENSP00000231509.3 UniProt:
	NR3C1 ENST00000504572.5	TSL:1	c.66G>A p.Glu22Glu	synonymous	Exon 3 of 10	Prot: ENSP00000422518.1 UniProt:

NR3C1 ENST00000394464.7

TSL:1MANE Select

HGVSc / HGVSpc.66G>Ap.Glu22Glu

Exon rankExon 2 of 9

synonymous

Prot: ENSP00000377977.2UniProt: P04150-1

NR3C1 ENST00000231509.7

TSL:1

HGVSc / HGVSpc.66G>Ap.Glu22Glu

Exon rankExon 2 of 9

synonymous

Prot: ENSP00000231509.3UniProt: P04150-3

NR3C1 ENST00000504572.5

TSL:1

HGVSc / HGVSpc.66G>Ap.Glu22Glu

Exon rankExon 3 of 10

synonymous

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:152190	Cov:32
GnomAD2 exomes	AF: 0.0183	AC:4603	Hom:	AN:251466	Cov:
GnomAD4 exome	AF: 0.0248	AC:36200	Hom:548	AN:1461842	Cov:32
GnomAD4 genome	AF: 0.0166	AC:2535	Hom:42	AN:152308	Cov:32
TOPMed (Bravo)	AF: 0.0149	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0213	AC:6666	Hom:99	AN:312912	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: 0.0209	AC:272	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: 0.0000330	AC:4	Hom:0	AN:122776	Cov:
Turkish Variome	AF: 0.0214	AC:143	Hom:0	AN:6686	Cov:
UK10K	AF: 0.0287	AC:217	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000446	AC:4	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	891	41958	0.0231	1545	66888
SCHEMA(Schizophrenia)	0.0176	2153	122104	0.0204	3898	191426

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	Glucocorticoid resistance (2)
-	-	2	not provided (2)
-	-	1	NR3C1-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	4.3
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.1
DANN	Benign	0.82
GPN-Star LLR	N/A	-1.9
GPN-Star score	N/A	1.9
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	0.39
PromoterAI	N/A	0.070	Neutral

Showing 9 of 9 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: rs6189;

hg19: chr5-142780339;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar