rs786205528

Variant names:

• chr2-96115486-G-A
• rs786205528
• NM_000682.7:c.664C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-96115486-G-A
• chr2-96115486-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000682.7(ADRA2B):​c.664C>T​(p.Arg222*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ADRA2B NM_000682.7 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 0.0530
• Publications: 4 publications found

Genes affected

ADRA2B (HGNC:282): (adrenoceptor alpha 2B) This intronless gene encodes a seven-pass transmembrane protein. This protein is a member of a subfamily of G protein-coupled receptors that regulate neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system. [provided by RefSeq, Apr 2014]

ADRA2B Gene-Disease associations (from GenCC):

• benign adult familial myoclonic epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P
• epilepsy, familial adult myoclonic, 2

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-96115486-G-A is Pathogenic according to our data. Variant chr2-96115486-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191117.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000682.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADRA2B	NM_000682.7	MANE Select	c.664C>T	p.Arg222*	stop_gained	Exon 1 of 1	NP_000673.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADRA2B	ENST00000620793.2	TSL:6 MANE Select	c.664C>T	p.Arg222*	stop_gained	Exon 1 of 1	ENSP00000480573.1	P18089

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461182 Hom.: 0 Cov.: 38 AF XY: 0.00000550 AC XY: 4 AN XY: 726892

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52958

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111836

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 33

Alfa AF: 0.00120 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Epilepsy, familial adult myoclonic, 2 (1)
1	-	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Benign	0.94
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.059	N
PhyloP100		0.053
Vest4		0.53
GERP RS		-2.6
Mutation Taster		=158/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs786205528; hg19: chr2-96781225; COSMIC: COSV69787715;