rs1045280

Variant names:

• chr17-4719343-C-T
• rs1045280
• NM_004313.4:c.840C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_004313.4(ARRB2):​c.840C>T​(p.Ser280Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.687 in 1,613,788 control chromosomes in the GnomAD database, including 385,711 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 0.63 (31382 hom., cov: 32)
  • Exomes 𝑓: 0.69 (354329 hom.)
• Consequence: ARRB2 NM_004313.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.35
• Publications: 68 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP7: Synonymous conserved (PhyloP=-1.35 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.795 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARRB2	NM_004313.4	c.840C>T	p.Ser280Ser	synonymous_variant	Exon 11 of 15	ENST00000269260.7	NP_004304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARRB2	ENST00000269260.7	c.840C>T	p.Ser280Ser	synonymous_variant	Exon 11 of 15	1	NM_004313.4	ENSP00000269260.2

Frequencies

GnomAD3 genomes AF: 0.630 AC: 95723 AN: 151942 Hom.: 31355 Cov.: 32

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.689

Gnomad ASJ AF: 0.680

Gnomad EAS AF: 0.816

Gnomad SAS AF: 0.810

Gnomad FIN AF: 0.769

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.687

Gnomad OTH AF: 0.618

GnomAD2 exomes AF: 0.710 AC: 178456 AN: 251324 AF XY: 0.715

Gnomad AFR exome AF: 0.434

Gnomad AMR exome AF: 0.763

Gnomad ASJ exome AF: 0.680

Gnomad EAS exome AF: 0.809

Gnomad FIN exome AF: 0.771

Gnomad NFE exome AF: 0.686

Gnomad OTH exome AF: 0.690

GnomAD4 exome AF: 0.693 AC: 1013075 AN: 1461728 Hom.: 354329 Cov.: 63 AF XY: 0.697 AC XY: 507073 AN XY: 727176

African (AFR) AF: 0.427 AC: 14285 AN: 33478

American (AMR) AF: 0.756 AC: 33792 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 17687 AN: 26118

East Asian (EAS) AF: 0.842 AC: 33423 AN: 39698

South Asian (SAS) AF: 0.793 AC: 68418 AN: 86250

European-Finnish (FIN) AF: 0.767 AC: 40986 AN: 53406

Middle Eastern (MID) AF: 0.600 AC: 3459 AN: 5768

European-Non Finnish (NFE) AF: 0.684 AC: 760443 AN: 1111904

Other (OTH) AF: 0.672 AC: 40582 AN: 60392

GnomAD4 genome AF: 0.630 AC: 95783 AN: 152060 Hom.: 31382 Cov.: 32 AF XY: 0.638 AC XY: 47393 AN XY: 74336

African (AFR) AF: 0.434 AC: 17980 AN: 41434

American (AMR) AF: 0.689 AC: 10531 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.680 AC: 2362 AN: 3472

East Asian (EAS) AF: 0.816 AC: 4211 AN: 5162

South Asian (SAS) AF: 0.811 AC: 3915 AN: 4828

European-Finnish (FIN) AF: 0.769 AC: 8144 AN: 10586

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.687 AC: 46710 AN: 67986

Other (OTH) AF: 0.622 AC: 1311 AN: 2108

Alfa AF: 0.667 Hom.: 139125

Bravo AF: 0.613

Asia WGS AF: 0.794 AC: 2761 AN: 3478

EpiCase AF: 0.671

EpiControl AF: 0.681

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	3.3
DANN	Benign	0.75
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1045280; hg19: chr17-4622638; COSMIC: COSV108056310; COSMIC: COSV108056310;