chr12-95022395-C-T

Variant names:

• chr12-95022395-C-T
• rs777227647
• NM_003297.4:c.1646G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003297.4(NR2C1):​c.1646G>A​(p.Arg549Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,601,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NR2C1 NM_003297.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.99
• Publications: 0 publications found

Genes affected

NR2C1 (HGNC:7971): (nuclear receptor subfamily 2 group C member 1) This gene encodes a nuclear hormone receptor characterized by a highly conserved DNA binding domain (DBD), a variable hinge region, and a carboxy-terminal ligand binding domain (LBD) that is typical for all members of the steroid/thyroid hormone receptor superfamily. This protein also belongs to a large family of ligand-inducible transcription factors that regulate gene expression by binding to specific DNA sequences within promoters of target genes. Multiple alternatively spliced transcript variants have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20666781).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003297.4. 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
	NR2C1	NM_003297.4	MANE Select	c.1646G>A	p.Arg549Lys	missense	Exon 14 of 14	NP_003288.2	P13056-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2C1	ENST00000333003.10	TSL:2 MANE Select	c.1646G>A	p.Arg549Lys	missense	Exon 14 of 14	ENSP00000333275.4	P13056-1
	NR2C1	ENST00000922903.1		c.1778G>A	p.Arg593Lys	missense	Exon 15 of 15	ENSP00000592962.1
	NR2C1	ENST00000922904.1		c.1778G>A	p.Arg593Lys	missense	Exon 15 of 15	ENSP00000592963.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151906 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000422 AC: 1 AN: 236774 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000919

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449584 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 720980

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32640

American (AMR) AF: 0.00 AC: 0 AN: 40844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25790

East Asian (EAS) AF: 0.00 AC: 0 AN: 39474

South Asian (SAS) AF: 0.00 AC: 0 AN: 83354

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109252

Other (OTH) AF: 0.00 AC: 0 AN: 59934

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151906 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74162

African (AFR) AF: 0.00 AC: 0 AN: 41296

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	20
DANN	Benign	0.65
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	-0.020	N
PhyloP100		3.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.62	N
REVEL	Uncertain	0.35
Sift	Benign	0.37	T
Sift4G	Benign	0.89	T
Polyphen		0.0020	B
Vest4		0.12
MutPred		0.56		Gain of catalytic residue at R549 (P = 0.0032)
MVP		0.26
MPC		0.19
ClinPred		0.63	D
GERP RS		4.7
Varity_R		0.18
gMVP		0.37
Mutation Taster		=90/10	polymorphism

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: rs777227647; hg19: chr12-95416171;