12-95049157-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_003297.4(NR2C1):​c.1042G>A​(p.Gly348Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

NR2C1
NM_003297.4 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.78
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.31838083).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NR2C1NM_003297.4 linkc.1042G>A p.Gly348Arg missense_variant Exon 9 of 14 ENST00000333003.10 NP_003288.2 P13056-1H9NIM2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NR2C1ENST00000333003.10 linkc.1042G>A p.Gly348Arg missense_variant Exon 9 of 14 2 NM_003297.4 ENSP00000333275.4 P13056-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152192
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000636
AC:
16
AN:
251476
Hom.:
0
AF XY:
0.0000662
AC XY:
9
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000867
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000105
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000219
AC:
32
AN:
1461822
Hom.:
0
Cov.:
31
AF XY:
0.0000261
AC XY:
19
AN XY:
727214
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000171
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152192
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000741
AC:
9
EpiCase
AF:
0.00
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 07, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1042G>A (p.G348R) alteration is located in exon 9 (coding exon 8) of the NR2C1 gene. This alteration results from a G to A substitution at nucleotide position 1042, causing the glycine (G) at amino acid position 348 to be replaced by an arginine (R). 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
0.19
BayesDel_addAF
Benign
-0.062
T
BayesDel_noAF
Benign
-0.11
CADD
Benign
23
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.31
T;T;.;.
Eigen
Uncertain
0.22
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.93
D;D;D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Benign
0.32
T;T;T;T
MetaSVM
Uncertain
0.23
D
MutationAssessor
Benign
1.8
L;.;L;L
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-2.0
N;.;N;N
REVEL
Uncertain
0.37
Sift
Uncertain
0.014
D;.;T;T
Sift4G
Uncertain
0.028
D;T;T;D
Polyphen
0.44
B;.;P;P
Vest4
0.43
MutPred
0.45
Gain of catalytic residue at A344 (P = 0.0018);Gain of catalytic residue at A344 (P = 0.0018);Gain of catalytic residue at A344 (P = 0.0018);Gain of catalytic residue at A344 (P = 0.0018);
MVP
0.45
MPC
0.31
ClinPred
0.090
T
GERP RS
6.0
Varity_R
0.054
gMVP
0.37

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs373219287; hg19: chr12-95442933; API