12-95040485-T-C

Variant names:

• chr12-95040485-T-C
• rs762240406
• NM_003297.4:c.1244A>G

Variant summary

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

The NM_003297.4(NR2C1):​c.1244A>G​(p.Gln415Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q415L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NR2C1 NM_003297.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.95
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1244A>G	p.Gln415Arg	missense	Exon 10 of 14	NP_003288.2	P13056-1
	NR2C1	NM_001127362.2		c.1244A>G	p.Gln415Arg	missense	Exon 10 of 12	NP_001120834.1	P13056-3
	NR2C1	NM_001032287.3		c.1244A>G	p.Gln415Arg	missense	Exon 10 of 12	NP_001027458.1	H9NIM3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2C1	ENST00000333003.10	TSL:2 MANE Select	c.1244A>G	p.Gln415Arg	missense	Exon 10 of 14	ENSP00000333275.4	P13056-1
	NR2C1	ENST00000393101.7	TSL:1	c.1244A>G	p.Gln415Arg	missense	Exon 10 of 12	ENSP00000376813.3	P13056-2
	NR2C1	ENST00000545833.5	TSL:1	n.1244A>G		non_coding_transcript_exon	Exon 9 of 10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.78
Sift	Uncertain	0.020	D
Sift4G	Benign	0.10	T
Polyphen		0.99	D
Vest4		0.47
MutPred		0.54		Gain of catalytic residue at Q415 (P = 0.011)
MVP		0.74
MPC		0.28
ClinPred		0.78	D
GERP RS		6.1
PromoterAI		0.055	Neutral
Varity_R		0.32
gMVP		0.67
Mutation Taster		=57/43	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: rs762240406; hg19: chr12-95434261;