rs6194

Variant names:

• chr5-143298796-G-A
• rs6194
• NM_000176.3:c.1764C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-143298796-G-A
• chr5-143298796-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000176.3(NR3C1):​c.1764C>T​(p.His588His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 1,613,416 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (129 hom.)
• Consequence: NR3C1 NM_000176.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.09
• Publications: 16 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 5-143298796-G-A is Benign according to our data. Variant chr5-143298796-G-A is described in ClinVar as Benign. ClinVar VariationId is 351368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.065 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.1764C>T	p.His588His	synonymous	Exon 6 of 9	NP_000167.1	P04150-1
	NR3C1	NM_001024094.2		c.1767C>T	p.His589His	synonymous	Exon 6 of 9	NP_001019265.1	E5KQF6
	NR3C1	NM_001364183.2		c.1767C>T	p.His589His	synonymous	Exon 7 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.1764C>T	p.His588His	synonymous	Exon 6 of 9	ENSP00000377977.2	P04150-1
	NR3C1	ENST00000231509.7	TSL:1	c.1767C>T	p.His589His	synonymous	Exon 6 of 9	ENSP00000231509.3	P04150-3
	NR3C1	ENST00000504572.5	TSL:1	c.1767C>T	p.His589His	synonymous	Exon 7 of 10	ENSP00000422518.1	P04150-3

Frequencies

GnomAD3 genomes AF: 0.00480 AC: 729 AN: 151988 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.000798

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0710

Gnomad SAS AF: 0.00996

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00836 AC: 2099 AN: 251198 AF XY: 0.00802

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0700

Gnomad FIN exome AF: 0.0202

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00342 AC: 4996 AN: 1461310 Hom.: 129 Cov.: 32 AF XY: 0.00347 AC XY: 2525 AN XY: 726974

African (AFR) AF: 0.000448 AC: 15 AN: 33462

American (AMR) AF: 0.000179 AC: 8 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0697 AC: 2765 AN: 39664

South Asian (SAS) AF: 0.00892 AC: 769 AN: 86246

European-Finnish (FIN) AF: 0.0192 AC: 1022 AN: 53220

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.0000872 AC: 97 AN: 1111764

Other (OTH) AF: 0.00522 AC: 315 AN: 60356

GnomAD4 genome AF: 0.00478 AC: 727 AN: 152106 Hom.: 21 Cov.: 32 AF XY: 0.00628 AC XY: 467 AN XY: 74336

African (AFR) AF: 0.000796 AC: 33 AN: 41476

American (AMR) AF: 0.000850 AC: 13 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0710 AC: 367 AN: 5168

South Asian (SAS) AF: 0.00976 AC: 47 AN: 4814

European-Finnish (FIN) AF: 0.0225 AC: 238 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68000

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00256 Hom.: 18

Bravo AF: 0.00314

Asia WGS AF: 0.0460 AC: 161 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

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	-0.44
CADD	Benign	5.9
DANN	Benign	0.69
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	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: rs6194; hg19: chr5-142678361; COSMIC: COSV99196093; COSMIC: COSV99196093;