rs6196

Variant names:

• chr5-143281925-A-G
• rs6196
• NM_000176.3:c.2298T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000176.3(NR3C1):​c.2298T>C​(p.Asn766Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,613,080 control chromosomes in the GnomAD database, including 19,890 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1921 hom., cov: 31)
  • Exomes 𝑓: 0.15 (17969 hom.)
• Consequence: NR3C1 NM_000176.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.67
• Publications: 79 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: Orphanet, Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000300303 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 5-143281925-A-G is Benign according to our data. Variant chr5-143281925-A-G is described in ClinVar as Benign. ClinVar VariationId is 351364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.67 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000176.3. 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
	NR3C1	NM_000176.3	MANE Select	c.2298T>C	p.Asn766Asn	synonymous	Exon 9 of 9	NP_000167.1	P04150-1
	NR3C1	NM_001024094.2		c.2301T>C	p.Asn767Asn	synonymous	Exon 9 of 9	NP_001019265.1	E5KQF6
	NR3C1	NM_001364183.2		c.2301T>C	p.Asn767Asn	synonymous	Exon 10 of 10	NP_001351112.1	P04150-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000394464.7	TSL:1 MANE Select	c.2298T>C	p.Asn766Asn	synonymous	Exon 9 of 9	ENSP00000377977.2	P04150-1
	NR3C1	ENST00000231509.7	TSL:1	c.2301T>C	p.Asn767Asn	synonymous	Exon 9 of 9	ENSP00000231509.3	P04150-3
	NR3C1	ENST00000504572.5	TSL:1	c.2301T>C	p.Asn767Asn	synonymous	Exon 10 of 10	ENSP00000422518.1	P04150-3

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23036 AN: 152052 Hom.: 1917 Cov.: 31

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.0909

Gnomad ASJ AF: 0.0655

Gnomad EAS AF: 0.0725

Gnomad SAS AF: 0.0334

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.124 AC: 31150 AN: 250760 AF XY: 0.121

Gnomad AFR exome AF: 0.178

Gnomad AMR exome AF: 0.0648

Gnomad ASJ exome AF: 0.0705

Gnomad EAS exome AF: 0.0709

Gnomad FIN exome AF: 0.201

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.150 AC: 219156 AN: 1460910 Hom.: 17969 Cov.: 31 AF XY: 0.146 AC XY: 105980 AN XY: 726802

African (AFR) AF: 0.177 AC: 5926 AN: 33430

American (AMR) AF: 0.0704 AC: 3147 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0716 AC: 1870 AN: 26114

East Asian (EAS) AF: 0.0705 AC: 2792 AN: 39618

South Asian (SAS) AF: 0.0325 AC: 2805 AN: 86246

European-Finnish (FIN) AF: 0.203 AC: 10845 AN: 53384

Middle Eastern (MID) AF: 0.0257 AC: 148 AN: 5764

European-Non Finnish (NFE) AF: 0.165 AC: 183189 AN: 1111328

Other (OTH) AF: 0.140 AC: 8434 AN: 60350

GnomAD4 genome AF: 0.152 AC: 23070 AN: 152170 Hom.: 1921 Cov.: 31 AF XY: 0.150 AC XY: 11138 AN XY: 74396

African (AFR) AF: 0.178 AC: 7411 AN: 41526

American (AMR) AF: 0.0908 AC: 1388 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0655 AC: 227 AN: 3468

East Asian (EAS) AF: 0.0725 AC: 376 AN: 5186

South Asian (SAS) AF: 0.0324 AC: 156 AN: 4814

European-Finnish (FIN) AF: 0.203 AC: 2144 AN: 10582

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.160 AC: 10879 AN: 67992

Other (OTH) AF: 0.124 AC: 262 AN: 2110

Alfa AF: 0.149 Hom.: 6102

Bravo AF: 0.145

Asia WGS AF: 0.0740 AC: 258 AN: 3478

EpiCase AF: 0.145

EpiControl AF: 0.139

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Glucocorticoid resistance (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.8
DANN	Benign	0.68
PhyloP100		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs6196; hg19: chr5-142661490; COSMIC: COSV51543216;