1-26913429-C-G

Position:

• chr1-26913429-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021969.3(NR0B2):​c.512G>C​(p.Gly171Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0716 in 1,613,920 control chromosomes in the GnomAD database, including 4,438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.067 (375 hom., cov: 32)
  • Exomes 𝑓: 0.072 (4063 hom.)
• Consequence: NR0B2 NM_021969.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.90

Genes affected

NR0B2 (HGNC:7961): (nuclear receptor subfamily 0 group B member 2) The protein encoded by this gene is an unusual orphan receptor that contains a putative ligand-binding domain but lacks a conventional DNA-binding domain. The gene product is a member of the nuclear hormone receptor family, a group of transcription factors regulated by small hydrophobic hormones, a subset of which do not have known ligands and are referred to as orphan nuclear receptors. The protein has been shown to interact with retinoid and thyroid hormone receptors, inhibiting their ligand-dependent transcriptional activation. In addition, interaction with estrogen receptors has been demonstrated, leading to inhibition of function. Studies suggest that the protein represses nuclear hormone receptor-mediated transactivation via two separate steps: competition with coactivators and the direct effects of its transcriptional repressor function. [provided by RefSeq, Jul 2008]

NUDC (HGNC:8045): (nuclear distribution C, dynein complex regulator) This gene encodes a nuclear distribution protein that plays an essential role in mitosis and cytokinesis. The encoded protein is involved in spindle formation during mitosis and in microtubule organization during cytokinesis. Pseudogenes of this gene are found on chromosome 2. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006049454).
• BP6: Variant 1-26913429-C-G is Benign according to our data. Variant chr1-26913429-C-G is described in ClinVar as [Benign]. Clinvar id is 595423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR0B2	NM_021969.3	c.512G>C	p.Gly171Ala	missense_variant	1/2	ENST00000254227.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR0B2	ENST00000254227.4	c.512G>C	p.Gly171Ala	missense_variant	1/2	1	NM_021969.3	P1
NUDC	ENST00000435827.6	c.93+2194C>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0670 AC: 10184 AN: 152008 Hom.: 374 Cov.: 32

Gnomad AFR AF: 0.0612

Gnomad AMI AF: 0.0604

Gnomad AMR AF: 0.0565

Gnomad ASJ AF: 0.0461

Gnomad EAS AF: 0.00367

Gnomad SAS AF: 0.0448

Gnomad FIN AF: 0.0828

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0784

Gnomad OTH AF: 0.0570

GnomAD3 exomes AF: 0.0592 AC: 14861 AN: 251016 Hom.: 520 AF XY: 0.0594 AC XY: 8059 AN XY: 135686

Gnomad AFR exome AF: 0.0639

Gnomad AMR exome AF: 0.0293

Gnomad ASJ exome AF: 0.0477

Gnomad EAS exome AF: 0.00359

Gnomad SAS exome AF: 0.0435

Gnomad FIN exome AF: 0.0765

Gnomad NFE exome AF: 0.0786

Gnomad OTH exome AF: 0.0600

GnomAD4 exome AF: 0.0721 AC: 105376 AN: 1461794 Hom.: 4063 Cov.: 32 AF XY: 0.0711 AC XY: 51683 AN XY: 727204

Gnomad4 AFR exome AF: 0.0645

Gnomad4 AMR exome AF: 0.0321

Gnomad4 ASJ exome AF: 0.0505

Gnomad4 EAS exome AF: 0.00202

Gnomad4 SAS exome AF: 0.0430

Gnomad4 FIN exome AF: 0.0764

Gnomad4 NFE exome AF: 0.0795

Gnomad4 OTH exome AF: 0.0655

GnomAD4 genome AF: 0.0670 AC: 10189 AN: 152126 Hom.: 375 Cov.: 32 AF XY: 0.0663 AC XY: 4932 AN XY: 74378

Gnomad4 AFR AF: 0.0611

Gnomad4 AMR AF: 0.0563

Gnomad4 ASJ AF: 0.0461

Gnomad4 EAS AF: 0.00367

Gnomad4 SAS AF: 0.0450

Gnomad4 FIN AF: 0.0828

Gnomad4 NFE AF: 0.0784

Gnomad4 OTH AF: 0.0583

Alfa AF: 0.0645 Hom.: 238

Bravo AF: 0.0647

TwinsUK AF: 0.0885 AC: 328

ALSPAC AF: 0.0786 AC: 303

ESP6500AA AF: 0.0617 AC: 272

ESP6500EA AF: 0.0813 AC: 699

ExAC AF: 0.0614 AC: 7461

Asia WGS AF: 0.0400 AC: 138 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 19, 2017

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.091	T
Polyphen		0.99	D
Vest4		0.20
MPC		0.34
ClinPred		0.032	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.67

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

Other links and lift over

dbSNP: rs6659176; hg19: chr1-27239920; COSMIC: COSV54259638;