chr12-95049226-C-T

Variant names:

• chr12-95049226-C-T
• rs142368782
• NM_003297.4:c.973G>A

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17

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 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
NR2C1	NM_003297.4	c.973G>A	p.Asp325Asn	missense_variant	Exon 9 of 14	ENST00000333003.10	NP_003288.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR2C1	ENST00000333003.10	c.973G>A	p.Asp325Asn	missense_variant	Exon 9 of 14	2	NM_003297.4	ENSP00000333275.4

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152090 Hom.: 1 Cov.: 32

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

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

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

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

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

Other links and lift over

dbSNP: rs142368782; hg19: chr12-95443002;