12-95051929-C-A

Variant names:

• chr12-95051929-C-A
• rs1456536204
• NM_003297.4:c.798G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003297.4(NR2C1):​c.798G>T​(p.Gln266His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000421 in 1,425,308 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: NR2C1 NM_003297.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.487

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23037529).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR2C1	NM_003297.4	c.798G>T	p.Gln266His	missense_variant	Exon 8 of 14	ENST00000333003.10	NP_003288.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR2C1	ENST00000333003.10	c.798G>T	p.Gln266His	missense_variant	Exon 8 of 14	2	NM_003297.4	ENSP00000333275.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000421 AC: 6 AN: 1425308 Hom.: 0 Cov.: 30 AF XY: 0.00000424 AC XY: 3 AN XY: 707978

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000546

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.798G>T (p.Q266H) alteration is located in exon 8 (coding exon 7) of the NR2C1 gene. This alteration results from a G to T substitution at nucleotide position 798, causing the glutamine (Q) at amino acid position 266 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;T;.;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.3	M;.;M;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.2	N;.;N;N
REVEL	Pathogenic	0.65
Sift	Benign	0.036	D;.;D;D
Sift4G	Benign	0.31	T;T;T;T
Polyphen		1.0	D;.;D;D
Vest4		0.33
MutPred		0.38		Gain of catalytic residue at G267 (P = 0.0226);Gain of catalytic residue at G267 (P = 0.0226);Gain of catalytic residue at G267 (P = 0.0226);Gain of catalytic residue at G267 (P = 0.0226);
MVP		0.58
MPC		0.71
ClinPred		0.76	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.097
gMVP		0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs1456536204; hg19: chr12-95445705;