2-156325082-TTTA-T

Position:

• chr2-156325082-TTTA-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The ENST00000426264.5(NR4A2):​c.*659_*661delTAA variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 153,192 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: NR4A2 ENST00000426264.5 splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.24

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 -9 ACMG points.

• BP6: Variant 2-156325082-TTTA-T is Benign according to our data. Variant chr2-156325082-TTTA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 331652.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00115 (175/152340) while in subpopulation NFE AF= 0.00168 (114/68038). AF 95% confidence interval is 0.00143. There are 0 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 175 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR4A2	NM_006186.4	c.*659_*661delTAA		3_prime_UTR_variant	8/8	ENST00000339562.9	NP_006177.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR4A2	ENST00000339562	c.*659_*661delTAA		3_prime_UTR_variant	8/8	1	NM_006186.4	ENSP00000344479.4

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 175 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.00334

GnomAD4 exome AF: 0.00117 AC: 1 AN: 852 Hom.: 0 AF XY: 0.00223 AC XY: 1 AN XY: 448

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00235

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.00102 AC XY: 76 AN XY: 74502

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00168

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.00142

Asia WGS AF: 0.000578 AC: 2 AN: 3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Parkinson Disease, Dominant/Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

NR4A2: BS1 -

Computational scores

Source: dbNSFP v4.3

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: rs577936871; hg19: chr2-157181594;