3-23962081-C-A

Variant summary

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

The NM_005126.5(NR1D2):​c.622C>A​(p.Gln208Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

NR1D2
NM_005126.5 missense

Scores

1
5
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.73
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]

Genome browser will be placed here

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=0.11919701).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NR1D2NM_005126.5 linkc.622C>A p.Gln208Lys missense_variant Exon 5 of 8 ENST00000312521.9 NP_005117.3 Q14995F1D8P2
NR1D2NM_001145425.2 linkc.397C>A p.Gln133Lys missense_variant Exon 5 of 8 NP_001138897.1 B4DXD3
NR1D2XM_006713451.4 linkc.622C>A p.Gln208Lys missense_variant Exon 5 of 7 XP_006713514.1
NR1D2NR_110524.2 linkn.915C>A 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.622C>A p.Gln208Lys missense_variant Exon 5 of 8 1 NM_005126.5 ENSP00000310006.3 Q14995
NR1D2ENST00000383773.8 linkn.622C>A non_coding_transcript_exon_variant Exon 5 of 9 1 ENSP00000373283.3 Q6NSM0
NR1D2ENST00000468700.1 linkn.626C>A non_coding_transcript_exon_variant Exon 4 of 4 3
NR1D2ENST00000492552.5 linkn.739C>A non_coding_transcript_exon_variant Exon 5 of 8 2 ENSP00000520893.1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152176
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251188
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135782
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1461846
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.0000144
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152176
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 05, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.622C>A (p.Q208K) alteration is located in exon 5 (coding exon 5) of the NR1D2 gene. This alteration results from a C to A substitution at nucleotide position 622, causing the glutamine (Q) at amino acid position 208 to be replaced by a lysine (K). 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
0.083
BayesDel_addAF
Uncertain
0.069
D
BayesDel_noAF
Benign
-0.14
CADD
Benign
20
DANN
Benign
0.60
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.053
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
D
M_CAP
Uncertain
0.099
D
MetaRNN
Benign
0.12
T
MetaSVM
Uncertain
-0.029
T
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-0.44
N
REVEL
Uncertain
0.39
Sift
Benign
0.81
T
Sift4G
Benign
0.92
T
Vest4
0.14
MutPred
0.35
Gain of ubiquitination at Q208 (P = 0.0039);
MVP
0.61
MPC
0.28
ClinPred
0.22
T
GERP RS
6.0
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs776628424; hg19: chr3-24003572; API