2-156329455-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006186.4(NR4A2):c.732C>A(p.Leu244=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000839 in 1,608,200 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (11 hom.)
• Consequence: NR4A2 NM_006186.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.686

Genes affected

NR4A2 (HGNC:7981): (nuclear receptor subfamily 4 group A member 2) This gene encodes a member of the steroid-thyroid hormone-retinoid receptor superfamily. The encoded protein may act as a transcription factor. Mutations in this gene have been associated with disorders related to dopaminergic dysfunction, including Parkinson disease, schizophernia, and manic depression. Misregulation of this gene may be associated with rheumatoid arthritis. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 2-156329455-G-T is Benign according to our data. Variant chr2-156329455-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 331661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.686 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00103 (157/152364) while in subpopulation NFE AF= 0.00162 (110/68030). AF 95% confidence interval is 0.00137. There are 0 homozygotes in gnomad4. There are 80 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 157 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR4A2	NM_006186.4	c.732C>A	p.Leu244=	synonymous_variant	3/8	ENST00000339562.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR4A2	ENST00000339562.9	c.732C>A	p.Leu244=	synonymous_variant	3/8	1	NM_006186.4	P1

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 157 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

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: 0.00414

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00102 AC: 246 AN: 240672 Hom.: 1 AF XY: 0.00108 AC XY: 142 AN XY: 131558

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000584

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00451

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.00152

GnomAD4 exome AF: 0.000819 AC: 1193 AN: 1455836 Hom.: 11 Cov.: 33 AF XY: 0.000891 AC XY: 645 AN XY: 724300

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00492

Gnomad4 NFE exome AF: 0.000813

Gnomad4 OTH exome AF: 0.000731

GnomAD4 genome AF: 0.00103 AC: 157 AN: 152364 Hom.: 0 Cov.: 32 AF XY: 0.00107 AC XY: 80 AN XY: 74514

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00414

Gnomad4 NFE AF: 0.00162

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00112 Hom.: 0

Bravo AF: 0.000563

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00137

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	NR4A2: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Parkinson disease, late-onset Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

NR4A2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 08, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	2.5
Dann	Benign	0.91

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: rs16840266; hg19: chr2-157185967;