12-95051828-C-T

Variant names:

• chr12-95051828-C-T
• NM_003297.4:c.899G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003297.4(NR2C1):​c.899G>A​(p.Ser300Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NR2C1 NM_003297.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00800
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05363044).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003297.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2C1	NM_003297.4	MANE Select	c.899G>A	p.Ser300Asn	missense	Exon 8 of 14	NP_003288.2	P13056-1
	NR2C1	NM_001127362.2		c.899G>A	p.Ser300Asn	missense	Exon 8 of 12	NP_001120834.1	P13056-3
	NR2C1	NM_001032287.3		c.899G>A	p.Ser300Asn	missense	Exon 8 of 12	NP_001027458.1	H9NIM3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2C1	ENST00000333003.10	TSL:2 MANE Select	c.899G>A	p.Ser300Asn	missense	Exon 8 of 14	ENSP00000333275.4	P13056-1
	NR2C1	ENST00000393101.7	TSL:1	c.899G>A	p.Ser300Asn	missense	Exon 8 of 12	ENSP00000376813.3	P13056-2
	NR2C1	ENST00000545833.5	TSL:1	n.899G>A		non_coding_transcript_exon	Exon 7 of 10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458490 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725594

African (AFR) AF: 0.00 AC: 0 AN: 33262

American (AMR) AF: 0.00 AC: 0 AN: 43464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.00 AC: 0 AN: 85704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111256

Other (OTH) AF: 0.00 AC: 0 AN: 60280

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.0080
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.24
Sift	Benign	0.26	T
Sift4G	Benign	0.28	T
Polyphen		0.0070	B
Vest4		0.11
MutPred		0.21		Loss of phosphorylation at S300 (P = 0.0228)
MVP		0.18
MPC		0.17
ClinPred		0.27	T
GERP RS		-1.0
Varity_R		0.034
gMVP		0.19
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr12-95445604;