5-143400774-C-A

Variant names:

• chr5-143400774-C-A
• rs6189
• NM_000176.3:c.66G>T
• NR3C1 p.Glu22Asp

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_000176.3(NR3C1):c.66G>T (p.Glu22Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,874 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.E22= (synonymous): Benign/Likely_benign (ClinVar VariationId 155925, 2 stars)

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NR3C1 NM_000176.3 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — very rare for AD+AR gene (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

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>T p.Glu22Asp	missense	Exon 2 of 9	Prot: NP_000167.1 UniProt:
	NR3C1 NM_001024094.2		c.66G>T p.Glu22Asp	missense	Exon 2 of 9	Prot: NP_001019265.1 UniProt:
	NR3C1 NM_001364183.2		c.66G>T p.Glu22Asp	missense	Exon 3 of 10	Prot: NP_001351112.1 UniProt:

NR3C1 NM_000176.3

MANE Select

HGVSc / HGVSpc.66G>Tp.Glu22Asp

Exon rankExon 2 of 9

missense

Prot: NP_000167.1UniProt: F1D8N4P04150-1

NR3C1 NM_001024094.2

HGVSc / HGVSpc.66G>Tp.Glu22Asp

Exon rankExon 2 of 9

missense

Prot: NP_001019265.1UniProt: E5KQF6P04150-3

NR3C1 NM_001364183.2

HGVSc / HGVSpc.66G>Tp.Glu22Asp

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.66G>T p.Glu22Asp	missense	Exon 2 of 9	Prot: ENSP00000377977.2 UniProt:
	NR3C1 ENST00000231509.7	TSL:1	c.66G>T p.Glu22Asp	missense	Exon 2 of 9	Prot: ENSP00000231509.3 UniProt:
	NR3C1 ENST00000504572.5	TSL:1	c.66G>T p.Glu22Asp	missense	Exon 3 of 10	Prot: ENSP00000422518.1 UniProt:

NR3C1 ENST00000394464.7

TSL:1MANE Select

HGVSc / HGVSpc.66G>Tp.Glu22Asp

Exon rankExon 2 of 9

missense

Prot: ENSP00000377977.2UniProt: P04150-1

NR3C1 ENST00000231509.7

TSL:1

HGVSc / HGVSpc.66G>Tp.Glu22Asp

Exon rankExon 2 of 9

missense

Prot: ENSP00000231509.3UniProt: P04150-3

NR3C1 ENST00000504572.5

TSL:1

HGVSc / HGVSpc.66G>Tp.Glu22Asp

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251466	Cov:
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461874	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 4 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00	0	41958	0.0000150	1	66888
SCHEMA(Schizophrenia)	0.00	0	67038	0.00000760	1	131520

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	8.9
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.60	D
FuncVEP CTI	Benign	0.0046
GPN-Star LLR	N/A	-4.0
GPN-Star score	N/A	4.0
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.71	T
Mutation Taster	N/A	95/5	polymorphism
MutationAssessor	Benign	1.5	L
PhyloP100	Benign	0.39
popEVE	Benign	-3.2
PrimateAI	Benign	0.32	T
PromoterAI	N/A	-0.0090	Neutral
PROVEAN	Benign	0.020	N
REVEL	Benign	0.078
Sift	Benign	0.19	T
Sift4G	Benign	0.45	T
Varity_R	N/A	0.058
VESM-3B	Benign	-2.6

Showing 29 of 29 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