rs4522461

Variant names:

• chr17-4718478-T-G
• rs4522461
• NM_004313.4:c.706+133T>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 16 publications found

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]

ENSG00000302420 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004313.4. 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
	ARRB2	NM_004313.4	MANE Select	c.706+133T>G		intron	N/A	NP_004304.1	P32121-1
	ARRB2	NM_001257328.2		c.769+133T>G		intron	N/A	NP_001244257.1	P32121-4
	ARRB2	NM_001257330.2		c.706+133T>G		intron	N/A	NP_001244259.1	P32121-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARRB2	ENST00000269260.7	TSL:1 MANE Select	c.706+133T>G		intron	N/A	ENSP00000269260.2	P32121-1
	ARRB2	ENST00000574954.5	TSL:1	c.130+133T>G		intron	N/A	ENSP00000466344.1	Q68DZ5
	ARRB2	ENST00000412477.7	TSL:2	c.769+133T>G		intron	N/A	ENSP00000403701.3	P32121-4

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

African (AFR) AF: 0.894 AC: 23253 AN: 26018

American (AMR) AF: 0.889 AC: 36378 AN: 40934

Ashkenazi Jewish (ASJ) AF: 0.838 AC: 18017 AN: 21510

East Asian (EAS) AF: 1.00 AC: 37955 AN: 37970

South Asian (SAS) AF: 0.891 AC: 66676 AN: 74844

European-Finnish (FIN) AF: 0.814 AC: 35499 AN: 43604

Middle Eastern (MID) AF: 0.822 AC: 3707 AN: 4510

European-Non Finnish (NFE) AF: 0.763 AC: 607613 AN: 796224

Other (OTH) AF: 0.805 AC: 38741 AN: 48104

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

African (AFR) AF: 0.883 AC: 36616 AN: 41458

American (AMR) AF: 0.840 AC: 12833 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.838 AC: 2909 AN: 3472

East Asian (EAS) AF: 0.998 AC: 5145 AN: 5154

South Asian (SAS) AF: 0.911 AC: 4382 AN: 4812

European-Finnish (FIN) AF: 0.821 AC: 8677 AN: 10574

Middle Eastern (MID) AF: 0.764 AC: 223 AN: 292

European-Non Finnish (NFE) AF: 0.760 AC: 51658 AN: 67968

Other (OTH) AF: 0.813 AC: 1715 AN: 2110

Alfa AF: 0.807 Hom.: 39134

Bravo AF: 0.826

Asia WGS AF: 0.945 AC: 3284 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	11
DANN	Benign	0.82
PhyloP100		0.76
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4522461; hg19: chr17-4621773;