rs12803

Variant names:

• chr2-156325413-A-C
• rs12803
• NM_006186.4:c.*331T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-156325413-A-C
• chr2-156325413-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006186.4(NR4A2):​c.*331T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 363,146 control chromosomes in the GnomAD database, including 39,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (14020 hom., cov: 32)
  • Exomes 𝑓: 0.48 (25674 hom.)
• Consequence: NR4A2 NM_006186.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.90
• Publications: 23 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 2-156325413-A-C is Benign according to our data. Variant chr2-156325413-A-C is described in ClinVar as Benign. ClinVar VariationId is 331655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR4A2	NM_006186.4	c.*331T>G		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.*331T>G		3_prime_UTR_variant	Exon 8 of 8	1	NM_006186.4	ENSP00000344479.4

Frequencies

GnomAD3 genomes AF: 0.394 AC: 59795 AN: 151894 Hom.: 14022 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.503

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.552

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.402

GnomAD4 exome AF: 0.478 AC: 100910 AN: 211132 Hom.: 25674 Cov.: 0 AF XY: 0.473 AC XY: 54439 AN XY: 115038

African (AFR) AF: 0.152 AC: 921 AN: 6048

American (AMR) AF: 0.283 AC: 2804 AN: 9910

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 2485 AN: 5228

East Asian (EAS) AF: 0.170 AC: 1602 AN: 9420

South Asian (SAS) AF: 0.442 AC: 17239 AN: 39004

European-Finnish (FIN) AF: 0.559 AC: 5447 AN: 9736

Middle Eastern (MID) AF: 0.456 AC: 345 AN: 756

European-Non Finnish (NFE) AF: 0.539 AC: 64963 AN: 120460

Other (OTH) AF: 0.483 AC: 5104 AN: 10570

GnomAD4 genome AF: 0.393 AC: 59779 AN: 152014 Hom.: 14020 Cov.: 32 AF XY: 0.389 AC XY: 28903 AN XY: 74270

African (AFR) AF: 0.159 AC: 6605 AN: 41484

American (AMR) AF: 0.317 AC: 4831 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 1652 AN: 3472

East Asian (EAS) AF: 0.177 AC: 913 AN: 5172

South Asian (SAS) AF: 0.436 AC: 2100 AN: 4822

European-Finnish (FIN) AF: 0.552 AC: 5811 AN: 10528

Middle Eastern (MID) AF: 0.397 AC: 116 AN: 292

European-Non Finnish (NFE) AF: 0.536 AC: 36450 AN: 67960

Other (OTH) AF: 0.399 AC: 843 AN: 2112

Alfa AF: 0.469 Hom.: 25530

Bravo AF: 0.358

Asia WGS AF: 0.290 AC: 1009 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Parkinson disease, late-onset Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Benign	0.84
PhyloP100		2.9
Mutation Taster		=94/6	polymorphism (auto)

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: rs12803; hg19: chr2-157181925; COSMIC: COSV59894704; COSMIC: COSV59894704;