2-156325324-CTGTGTG-CTG

Variant names:

• chr2-156325324-CTGTG-C
• rs3832066
• NM_006186.4:c.*416_*419delCACA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_006186.4(NR4A2):​c.*416_*419delCACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00906 in 217,480 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000080 (0 hom., cov: 0)
  • Exomes 𝑓: 0.029 (0 hom.)
• Consequence: NR4A2 NM_006186.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR4A2	NM_006186.4	c.*416_*419delCACA		3_prime_UTR_variant	Exon 8 of 8	ENST00000339562.9	NP_006177.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR4A2	ENST00000339562.9	c.*416_*419delCACA		3_prime_UTR_variant	Exon 8 of 8	1	NM_006186.4	ENSP00000344479.4

Frequencies

GnomAD3 genomes AF: 0.0000799 AC: 12 AN: 150264 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.000296

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000889

Gnomad OTH AF: 0.000483

GnomAD4 exome AF: 0.0292 AC: 1958 AN: 67106 Hom.: 0 AF XY: 0.0292 AC XY: 1041 AN XY: 35606

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0109 AC: 26 AN: 2394

American (AMR) AF: 0.0109 AC: 40 AN: 3678

Ashkenazi Jewish (ASJ) AF: 0.0368 AC: 59 AN: 1604

East Asian (EAS) AF: 0.00495 AC: 20 AN: 4042

South Asian (SAS) AF: 0.0227 AC: 236 AN: 10416

European-Finnish (FIN) AF: 0.0311 AC: 87 AN: 2800

Middle Eastern (MID) AF: 0.0338 AC: 9 AN: 266

European-Non Finnish (NFE) AF: 0.0358 AC: 1378 AN: 38454

Other (OTH) AF: 0.0298 AC: 103 AN: 3452

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000798 AC: 12 AN: 150374 Hom.: 0 Cov.: 0 AF XY: 0.0000545 AC XY: 4 AN XY: 73408

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000244 AC: 1 AN: 41032

American (AMR) AF: 0.00 AC: 0 AN: 15094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.000210 AC: 1 AN: 4768

European-Finnish (FIN) AF: 0.000296 AC: 3 AN: 10138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000889 AC: 6 AN: 67466

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000175556), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 913

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs3832066; hg19: chr2-157181836;