Genetic Variant NM_005126.5:c.664C>T (chr3-23962123-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005126.5(NR1D2):c.664C>T(p.Pro222Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 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)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NR1D2
NM_005126.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.404

Variant links:

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]

NR1D2 links:

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ACMG classification

Classification made for transcript

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=0.104634196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1D2	NM_005126.5 link	c.664C>T	p.Pro222Ser	missense_variant	Exon 5 of 8	ENST00000312521.9	NP_005117.3	Q14995F1D8P2
NR1D2	NM_001145425.2 link	c.439C>T	p.Pro147Ser	missense_variant	Exon 5 of 8		NP_001138897.1	B4DXD3
NR1D2	XM_006713451.4 link	c.664C>T	p.Pro222Ser	missense_variant	Exon 5 of 7		XP_006713514.1
NR1D2	NR_110524.2 link	n.957C>T		non_coding_transcript_exon_variant	Exon 5 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NR1D2	ENST00000312521.9 link	c.664C>T	p.Pro222Ser	missense_variant	Exon 5 of 8	1	NM_005126.5	ENSP00000310006.3	Q14995
NR1D2	ENST00000383773.8 link	n.664C>T		non_coding_transcript_exon_variant	Exon 5 of 9	1		ENSP00000373283.3	Q6NSM0
NR1D2	ENST00000468700.1 link	n.668C>T		non_coding_transcript_exon_variant	Exon 4 of 4	3
NR1D2	ENST00000492552.5 link	n.781C>T		non_coding_transcript_exon_variant	Exon 5 of 8	2		ENSP00000520893.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.664C>T (p.P222S) alteration is located in exon 5 (coding exon 5) of the NR1D2 gene. This alteration results from a C to T substitution at nucleotide position 664, causing the proline (P) at amino acid position 222 to be replaced by a serine (S). 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

0.069

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.73

M_CAP

Benign

0.037

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.36

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.36

Sift

Benign

0.12

Sift4G

Benign

0.070

Vest4

0.10

MutPred

0.12

Gain of phosphorylation at P222 (P = 0.0609);

MVP

0.62

MPC

0.21

ClinPred

0.11

GERP RS

5.1

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over