rs4522461

Positions:

• chr17-4718478-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004313.4(ARRB2):​c.706+133T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.797 in 1,245,738 control chromosomes in the GnomAD database, including 398,394 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.82 (51450 hom., cov: 30)
  • Exomes 𝑓: 0.79 (346944 hom.)
• Consequence: ARRB2 NM_004313.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.760

Genes affected

ARRB2 (HGNC:712): (arrestin beta 2) Members of arrestin/beta-arrestin protein family are thought to participate in agonist-mediated desensitization of G-protein-coupled receptors and cause specific dampening of cellular responses to stimuli such as hormones, neurotransmitters, or sensory signals. Arrestin beta 2, like arrestin beta 1, was shown to inhibit beta-adrenergic receptor function in vitro. It is expressed at high levels in the central nervous system and may play a role in the regulation of synaptic receptors. Besides the brain, a cDNA for arrestin beta 2 was isolated from thyroid gland, and thus it may also be involved in hormone-specific desensitization of TSH receptors. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARRB2	NM_004313.4	c.706+133T>G		intron_variant		ENST00000269260.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARRB2	ENST00000269260.7	c.706+133T>G		intron_variant		1	NM_004313.4	P1

Frequencies

GnomAD3 genomes AF: 0.820 AC: 124582 AN: 151902 Hom.: 51384 Cov.: 30

Gnomad AFR AF: 0.883

Gnomad AMI AF: 0.607

Gnomad AMR AF: 0.840

Gnomad ASJ AF: 0.838

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.910

Gnomad FIN AF: 0.821

Gnomad MID AF: 0.761

Gnomad NFE AF: 0.760

Gnomad OTH AF: 0.811

GnomAD4 exome AF: 0.793 AC: 867839 AN: 1093718 Hom.: 346944 Cov.: 15 AF XY: 0.796 AC XY: 442926 AN XY: 556462

Gnomad4 AFR exome AF: 0.894

Gnomad4 AMR exome AF: 0.889

Gnomad4 ASJ exome AF: 0.838

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.891

Gnomad4 FIN exome AF: 0.814

Gnomad4 NFE exome AF: 0.763

Gnomad4 OTH exome AF: 0.805

GnomAD4 genome AF: 0.820 AC: 124709 AN: 152020 Hom.: 51450 Cov.: 30 AF XY: 0.826 AC XY: 61381 AN XY: 74294

Gnomad4 AFR AF: 0.883

Gnomad4 AMR AF: 0.840

Gnomad4 ASJ AF: 0.838

Gnomad4 EAS AF: 0.998

Gnomad4 SAS AF: 0.911

Gnomad4 FIN AF: 0.821

Gnomad4 NFE AF: 0.760

Gnomad4 OTH AF: 0.813

Alfa AF: 0.791 Hom.: 23609

Bravo AF: 0.826

Asia WGS AF: 0.945 AC: 3284 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	11
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs4522461; hg19: chr17-4621773;