2-156331633-C-T

Variant names:

• chr2-156331633-C-T
• rs834835
• NM_006186.4:c.-126-842G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006186.4(NR4A2):​c.-126-842G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.58 in 152,112 control chromosomes in the GnomAD database, including 27,472 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.58 (27472 hom., cov: 32)
• Consequence: NR4A2 NM_006186.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.113
• Publications: 11 publications found

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]

NR4A2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006186.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR4A2	NM_006186.4	MANE Select	c.-126-842G>A		intron	N/A	NP_006177.1
	NR4A2	NM_173173.3		c.-137-842G>A		intron	N/A	NP_775265.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR4A2	ENST00000339562.9	TSL:1 MANE Select	c.-126-842G>A		intron	N/A	ENSP00000344479.4
	NR4A2	ENST00000426264.5	TSL:1	c.-137-842G>A		intron	N/A	ENSP00000389986.1
	NR4A2	ENST00000424077.1	TSL:1	c.-3+847G>A		intron	N/A	ENSP00000406808.1

Frequencies

GnomAD3 genomes AF: 0.580 AC: 88134 AN: 151996 Hom.: 27464 Cov.: 32

Gnomad AFR AF: 0.356

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.522

Gnomad ASJ AF: 0.739

Gnomad EAS AF: 0.436

Gnomad SAS AF: 0.600

Gnomad FIN AF: 0.724

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.705

Gnomad OTH AF: 0.620

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.580 AC: 88152 AN: 152112 Hom.: 27472 Cov.: 32 AF XY: 0.580 AC XY: 43131 AN XY: 74334

African (AFR) AF: 0.355 AC: 14738 AN: 41472

American (AMR) AF: 0.522 AC: 7976 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.739 AC: 2565 AN: 3472

East Asian (EAS) AF: 0.435 AC: 2249 AN: 5170

South Asian (SAS) AF: 0.601 AC: 2898 AN: 4818

European-Finnish (FIN) AF: 0.724 AC: 7665 AN: 10588

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.705 AC: 47949 AN: 67980

Other (OTH) AF: 0.621 AC: 1313 AN: 2116

Alfa AF: 0.650 Hom.: 46012

Bravo AF: 0.547

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Benign	0.79
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs834835; hg19: chr2-157188145;