Genetic Variant NR1D2:p.Cys120Cys (chr3-23956113-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_005126.5(NR1D2):c.360C>T(p.Cys120Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00533 in 1,612,538 control chromosomes in the GnomAD database, including 399 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 211 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 188 hom. )

Consequence

NR1D2
NM_005126.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.43

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 Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 3-23956113-C-T is Benign according to our data. Variant chr3-23956113-C-T is described in ClinVar as [Benign]. Clinvar id is 775851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.43 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1D2	NM_005126.5 link	c.360C>T	p.Cys120Cys	synonymous_variant	Exon 3 of 8	ENST00000312521.9	NP_005117.3	Q14995F1D8P2
NR1D2	NM_001145425.2 link	c.135C>T	p.Cys45Cys	synonymous_variant	Exon 3 of 8		NP_001138897.1	B4DXD3
NR1D2	XM_006713451.4 link	c.360C>T	p.Cys120Cys	synonymous_variant	Exon 3 of 7		XP_006713514.1
NR1D2	NR_110524.2 link	n.653C>T		non_coding_transcript_exon_variant	Exon 3 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NR1D2	ENST00000312521.9 link	c.360C>T	p.Cys120Cys	synonymous_variant	Exon 3 of 8	1	NM_005126.5	ENSP00000310006.3	Q14995
NR1D2	ENST00000383773.8 link	n.360C>T		non_coding_transcript_exon_variant	Exon 3 of 9	1		ENSP00000373283.3	Q6NSM0
NR1D2	ENST00000468700.1 link	n.255C>T		non_coding_transcript_exon_variant	Exon 2 of 4	3
NR1D2	ENST00000492552.5 link	n.477C>T		non_coding_transcript_exon_variant	Exon 3 of 8	2		ENSP00000520893.1

Frequencies

GnomAD3 genomes

AF:

0.0271

AC:

4121

AN:

152036

Hom.:

211

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0938

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0104

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000823

Gnomad OTH

AF:

0.0129

GnomAD3 exomes

AF:

0.00752

AC:

1891

AN:

251460

Hom.:

AF XY:

0.00558

AC XY:

759

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.0984

Gnomad AMR exome

AF:

0.00532

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000615

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00306

AC:

4475

AN:

1460384

Hom.:

188

Cov.:

AF XY:

0.00269

AC XY:

1955

AN XY:

726602

show subpopulations

Gnomad4 AFR exome

AF:

0.0973

Gnomad4 AMR exome

AF:

0.00613

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000468

Gnomad4 OTH exome

AF:

0.00617

GnomAD4 genome

AF:

0.0271

AC:

4125

AN:

152154

Hom.:

211

Cov.:

AF XY:

0.0265

AC XY:

1972

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.0936

Gnomad4 AMR

AF:

0.0103

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000823

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.0122

Hom.:

Bravo

AF:

0.0314

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.000818

EpiControl

AF:

0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.53

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over