NM_000176.3:c.68_69delGGinsAA

Variant names:

• chr5-143400771-CC-TT
• NM_000176.3:c.68_69delGGinsAA
• NR3C1 p.Arg23Lys

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_000176.3(NR3C1):c.68_69delGGinsAA (p.Arg23Lys) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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.R23K: Benign/Likely_benign (ClinVar VariationId 351377, 2 stars); p.R23K: Uncertain_significance (ClinVar VariationId 1333751, 1 star) 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: not found (cov: 32)
• Consequence: NR3C1 NM_000176.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.77
• Publications: 0 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 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 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.68_69delGGinsAA p.Arg23Lys	missense	N/A	Prot: NP_000167.1 UniProt:
	NR3C1 NM_001024094.2		c.68_69delGGinsAA p.Arg23Lys	missense	N/A	Prot: NP_001019265.1 UniProt:
	NR3C1 NM_001364183.2		c.68_69delGGinsAA p.Arg23Lys	missense	N/A	Prot: NP_001351112.1 UniProt:

NR3C1 NM_000176.3

MANE Select

HGVSc / HGVSpc.68_69delGGinsAAp.Arg23Lys

Exon rankN/A

missense

Prot: NP_000167.1UniProt: F1D8N4P04150-1

NR3C1 NM_001024094.2

HGVSc / HGVSpc.68_69delGGinsAAp.Arg23Lys

Exon rankN/A

missense

Prot: NP_001019265.1UniProt: E5KQF6P04150-3

NR3C1 NM_001364183.2

HGVSc / HGVSpc.68_69delGGinsAAp.Arg23Lys

Exon rankN/A

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.68_69delGGinsAA p.Arg23Lys	missense	N/A	Prot: ENSP00000377977.2 UniProt:
	NR3C1 ENST00000231509.7	TSL:1	c.68_69delGGinsAA p.Arg23Lys	missense	N/A	Prot: ENSP00000231509.3 UniProt:
	NR3C1 ENST00000504572.5	TSL:1	c.68_69delGGinsAA p.Arg23Lys	missense	N/A	Prot: ENSP00000422518.1 UniProt:

NR3C1 ENST00000394464.7

TSL:1MANE Select

HGVSc / HGVSpc.68_69delGGinsAAp.Arg23Lys

Exon rankN/A

missense

Prot: ENSP00000377977.2UniProt: P04150-1

NR3C1 ENST00000231509.7

TSL:1

HGVSc / HGVSpc.68_69delGGinsAAp.Arg23Lys

Exon rankN/A

missense

Prot: ENSP00000231509.3UniProt: P04150-3

NR3C1 ENST00000504572.5

TSL:1

HGVSc / HGVSpc.68_69delGGinsAAp.Arg23Lys

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	3.8

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr5-142780336;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar