12-95040543-A-T

Variant names:

• chr12-95040543-A-T
• NM_003297.4:c.1186T>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003297.4(NR2C1):​c.1186T>A​(p.Ser396Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,666 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: 0.0000014 (0 hom.)
• Consequence: NR2C1 NM_003297.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.44

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3049455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR2C1	NM_003297.4	c.1186T>A	p.Ser396Thr	missense_variant	Exon 10 of 14	ENST00000333003.10	NP_003288.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR2C1	ENST00000333003.10	c.1186T>A	p.Ser396Thr	missense_variant	Exon 10 of 14	2	NM_003297.4	ENSP00000333275.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461666 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727156

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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

Dec 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1186T>A (p.S396T) alteration is located in exon 10 (coding exon 9) of the NR2C1 gene. This alteration results from a T to A substitution at nucleotide position 1186, causing the serine (S) at amino acid position 396 to be replaced by a threonine (T). 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	0.16
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;T;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.4	L;.;L;L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.3	N;.;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.21	T;.;T;T
Sift4G	Benign	0.50	T;T;T;T
Polyphen		0.0010	B;.;B;B
Vest4		0.39
MutPred		0.47		Gain of catalytic residue at S398 (P = 5e-04);Gain of catalytic residue at S398 (P = 5e-04);Gain of catalytic residue at S398 (P = 5e-04);Gain of catalytic residue at S398 (P = 5e-04);
MVP		0.53
MPC		0.18
ClinPred		0.65	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.091
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-95434319;