chr12-95049226-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003297.4(NR2C1):​c.973G>A​(p.Asp325Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000317 in 1,613,650 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00032 ( 1 hom. )

Consequence

NR2C1
NM_003297.4 missense

Scores

6
6
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.17
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 Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0769586).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NR2C1NM_003297.4 linkc.973G>A p.Asp325Asn 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.973G>A p.Asp325Asn missense_variant Exon 9 of 14 2 NM_003297.4 ENSP00000333275.4 P13056-1

Frequencies

GnomAD3 genomes
AF:
0.000302
AC:
46
AN:
152090
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
Gnomad ASJ
AF:
0.00375
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.000338
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.000399
AC:
100
AN:
250930
Hom.:
0
AF XY:
0.000376
AC XY:
51
AN XY:
135622
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000581
Gnomad ASJ exome
AF:
0.00398
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000164
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000458
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000319
AC:
466
AN:
1461442
Hom.:
1
Cov.:
31
AF XY:
0.000337
AC XY:
245
AN XY:
727014
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000896
Gnomad4 ASJ exome
AF:
0.00348
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000337
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000277
Gnomad4 OTH exome
AF:
0.000530
GnomAD4 genome
AF:
0.000302
AC:
46
AN:
152208
Hom.:
1
Cov.:
32
AF XY:
0.000336
AC XY:
25
AN XY:
74422
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00375
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000338
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.000526
Hom.:
1
Bravo
AF:
0.000340
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.000428
AC:
52
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000709
EpiControl
AF:
0.000948

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Aug 23, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.973G>A (p.D325N) 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 973, causing the aspartic acid (D) at amino acid position 325 to be replaced by an asparagine (N). 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
0.32
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.12
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.53
D;T;.;.
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D;D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.077
T;T;T;T
MetaSVM
Pathogenic
0.80
D
MutationAssessor
Uncertain
2.8
M;.;M;M
PrimateAI
Uncertain
0.71
T
PROVEAN
Uncertain
-2.9
D;.;D;D
REVEL
Uncertain
0.55
Sift
Benign
0.098
T;.;T;T
Sift4G
Benign
0.070
T;D;D;D
Polyphen
1.0
D;.;D;D
Vest4
0.63
MVP
0.74
MPC
0.18
ClinPred
0.13
T
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.36
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
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: rs142368782; hg19: chr12-95443002; API