17-4719343-C-T

Position:

• chr17-4719343-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_004313.4(ARRB2):​c.840C>T​(p.Ser280=) 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

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 -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/exons	MANE	Protein	UniProt
ARRB2	NM_004313.4	c.840C>T	p.Ser280=	synonymous_variant	11/15	ENST00000269260.7	NP_004304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARRB2	ENST00000269260.7	c.840C>T	p.Ser280=	synonymous_variant	11/15	1	NM_004313.4	ENSP00000269260	P1

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

GnomAD3 exomes AF: 0.710 AC: 178456 AN: 251324 Hom.: 64499 AF XY: 0.715 AC XY: 97059 AN XY: 135826

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 SAS exome AF: 0.796

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

Gnomad4 AFR exome AF: 0.427

Gnomad4 AMR exome AF: 0.756

Gnomad4 ASJ exome AF: 0.677

Gnomad4 EAS exome AF: 0.842

Gnomad4 SAS exome AF: 0.793

Gnomad4 FIN exome AF: 0.767

Gnomad4 NFE exome AF: 0.684

Gnomad4 OTH exome AF: 0.672

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

Gnomad4 AFR AF: 0.434

Gnomad4 AMR AF: 0.689

Gnomad4 ASJ AF: 0.680

Gnomad4 EAS AF: 0.816

Gnomad4 SAS AF: 0.811

Gnomad4 FIN AF: 0.769

Gnomad4 NFE AF: 0.687

Gnomad4 OTH AF: 0.622

Alfa AF: 0.672 Hom.: 67305

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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1045280; hg19: chr17-4622638;