NM_005126.5:c.664C>T

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

3
14

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]

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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
NR1D2NM_005126.5 linkc.664C>T p.Pro222Ser missense_variant Exon 5 of 8 ENST00000312521.9 NP_005117.3 Q14995F1D8P2
NR1D2NM_001145425.2 linkc.439C>T p.Pro147Ser missense_variant Exon 5 of 8 NP_001138897.1 B4DXD3
NR1D2XM_006713451.4 linkc.664C>T p.Pro222Ser missense_variant Exon 5 of 7 XP_006713514.1
NR1D2NR_110524.2 linkn.957C>T non_coding_transcript_exon_variant Exon 5 of 9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NR1D2ENST00000312521.9 linkc.664C>T p.Pro222Ser missense_variant Exon 5 of 8 1 NM_005126.5 ENSP00000310006.3 Q14995
NR1D2ENST00000383773.8 linkn.664C>T non_coding_transcript_exon_variant Exon 5 of 9 1 ENSP00000373283.3 Q6NSM0
NR1D2ENST00000468700.1 linkn.668C>T non_coding_transcript_exon_variant Exon 4 of 4 3
NR1D2ENST00000492552.5 linkn.781C>T non_coding_transcript_exon_variant Exon 5 of 8 2 ENSP00000520893.1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461856
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
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.:
32

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
T
BayesDel_noAF
Benign
-0.14
CADD
Benign
14
DANN
Uncertain
0.98
Eigen
Benign
-0.52
Eigen_PC
Benign
-0.40
FATHMM_MKL
Benign
0.73
D
LIST_S2
Benign
0.73
T
M_CAP
Benign
0.037
D
MetaRNN
Benign
0.10
T
MetaSVM
Benign
-0.36
T
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.1
N
REVEL
Uncertain
0.36
Sift
Benign
0.12
T
Sift4G
Benign
0.070
T
Vest4
0.10
MutPred
0.12
Gain of phosphorylation at P222 (P = 0.0609);
MVP
0.62
MPC
0.21
ClinPred
0.11
T
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.

Other links and lift over

hg19: chr3-24003614; API