3-23962115-C-G

Variant names:

• chr3-23962115-C-G
• NM_005126.5:c.656C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005126.5(NR1D2):​c.656C>G​(p.Thr219Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 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)
• Consequence: NR1D2 NM_005126.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.80

Genes affected

NR1D2 (HGNC:7963): (nuclear receptor subfamily 1 group D member 2) This gene encodes a member of the nuclear hormone receptor family, specifically the NR1 subfamily of receptors. The encoded protein functions as a transcriptional repressor and may play a role in circadian rhythms and carbohydrate and lipid metabolism. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11170003).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1D2	NM_005126.5	c.656C>G	p.Thr219Arg	missense_variant	Exon 5 of 8	ENST00000312521.9	NP_005117.3
NR1D2	NM_001145425.2	c.431C>G	p.Thr144Arg	missense_variant	Exon 5 of 8		NP_001138897.1
NR1D2	XM_006713451.4	c.656C>G	p.Thr219Arg	missense_variant	Exon 5 of 7		XP_006713514.1
NR1D2	NR_110524.2	n.949C>G		non_coding_transcript_exon_variant	Exon 5 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1D2	ENST00000312521.9	c.656C>G	p.Thr219Arg	missense_variant	Exon 5 of 8	1	NM_005126.5	ENSP00000310006.3
NR1D2	ENST00000383773.8	n.656C>G		non_coding_transcript_exon_variant	Exon 5 of 9	1		ENSP00000373283.3
NR1D2	ENST00000468700.1	n.660C>G		non_coding_transcript_exon_variant	Exon 4 of 4	3
NR1D2	ENST00000492552.5	n.773C>G		non_coding_transcript_exon_variant	Exon 5 of 8	2		ENSP00000520893.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.656C>G (p.T219R) alteration is located in exon 5 (coding exon 5) of the NR1D2 gene. This alteration results from a C to G substitution at nucleotide position 656, causing the threonine (T) at amino acid position 219 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	0.077
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	16
DANN	Uncertain	0.98
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.56	T
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.88	N
REVEL	Uncertain	0.31
Sift	Benign	0.051	T
Sift4G	Benign	0.46	T
Vest4		0.19
MutPred		0.15		Loss of glycosylation at T219 (P = 0.0764);
MVP		0.65
MPC		0.25
ClinPred		0.20	T
GERP RS		5.1
gMVP		0.36

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: chr3-24003606;