Genetic Variant NR4A2:c.*416_*419dupCACA (chr2-156325324-C-CTGTG) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_006186.4(NR4A2):c.*416_*419dupCACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00010 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

NR4A2
NM_006186.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.22

Publications

2 publications found

Variant links:

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

NR4A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000996 (15/150570) while in subpopulation AFR AF = 0.000341 (14/41036). AF 95% confidence interval is 0.000206. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR4A2	NM_006186.4 link	c.416_419dupCACA		3_prime_UTR_variant	Exon 8 of 8	ENST00000339562.9	NP_006177.1	P43354-1F1D8N6Q53EL4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR4A2	ENST00000339562.9 link	c.416_419dupCACA		3_prime_UTR_variant	Exon 8 of 8	1	NM_006186.4	ENSP00000344479.4		P43354-1

Frequencies

GnomAD3 genomes

AF:

0.0000997

AC:

AN:

150460

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000342

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000142

AC:

AN:

70492

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

37374

show subpopulations

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

African (AFR)

AF:

0.000408

AC:

AN:

2448

American (AMR)

AF:

0.00

AC:

AN:

3810

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1696

East Asian (EAS)

AF:

0.00

AC:

AN:

4108

South Asian (SAS)

AF:

0.00

AC:

AN:

10798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2932

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

40798

Other (OTH)

AF:

0.00

AC:

AN:

3626

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000996

AC:

AN:

150570

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

73500

show subpopulations

African (AFR)

AF:

0.000341

AC:

AN:

41036

American (AMR)

AF:

0.00

AC:

AN:

15100

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5130

South Asian (SAS)

AF:

0.00

AC:

AN:

4768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10236

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67552

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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2-156325324-CTGTGTG-CTGTGTGTGTG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over