NM_004313.4:c.54+134G>A

Variant names:

• chr17-4715177-G-A
• rs16954146
• NM_004313.4:c.54+134G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_004313.4(ARRB2):​c.54+134G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0356 in 1,050,348 control chromosomes in the GnomAD database, including 2,861 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 0.090 (1473 hom., cov: 30)
  • Exomes 𝑓: 0.026 (1388 hom.)
• Consequence: ARRB2 NM_004313.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.67
• Publications: 7 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]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARRB2	NM_004313.4	c.54+134G>A		intron_variant	Intron 2 of 14	ENST00000269260.7	NP_004304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARRB2	ENST00000269260.7	c.54+134G>A		intron_variant	Intron 2 of 14	1	NM_004313.4	ENSP00000269260.2

Frequencies

GnomAD3 genomes AF: 0.0895 AC: 13598 AN: 151962 Hom.: 1467 Cov.: 30

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0650

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.0530

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.0846

GnomAD2 exomes AF: 0.0703 AC: 5547 AN: 78856 AF XY: 0.0666

Gnomad AFR exome AF: 0.258

Gnomad AMR exome AF: 0.0874

Gnomad ASJ exome AF: 0.0521

Gnomad EAS exome AF: 0.201

Gnomad FIN exome AF: 0.00281

Gnomad NFE exome AF: 0.0141

Gnomad OTH exome AF: 0.0569

GnomAD4 exome AF: 0.0265 AC: 23775 AN: 898268 Hom.: 1388 Cov.: 11 AF XY: 0.0262 AC XY: 11773 AN XY: 449296

African (AFR) AF: 0.250 AC: 5063 AN: 20256

American (AMR) AF: 0.0780 AC: 1653 AN: 21180

Ashkenazi Jewish (ASJ) AF: 0.0431 AC: 717 AN: 16650

East Asian (EAS) AF: 0.151 AC: 4726 AN: 31304

South Asian (SAS) AF: 0.0452 AC: 2534 AN: 56100

European-Finnish (FIN) AF: 0.00358 AC: 150 AN: 41854

Middle Eastern (MID) AF: 0.0718 AC: 262 AN: 3648

European-Non Finnish (NFE) AF: 0.00994 AC: 6634 AN: 667314

Other (OTH) AF: 0.0509 AC: 2036 AN: 39962

GnomAD4 genome AF: 0.0896 AC: 13628 AN: 152080 Hom.: 1473 Cov.: 30 AF XY: 0.0891 AC XY: 6624 AN XY: 74330

African (AFR) AF: 0.247 AC: 10220 AN: 41460

American (AMR) AF: 0.0649 AC: 991 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 142 AN: 3472

East Asian (EAS) AF: 0.182 AC: 938 AN: 5148

South Asian (SAS) AF: 0.0533 AC: 257 AN: 4826

European-Finnish (FIN) AF: 0.00236 AC: 25 AN: 10600

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0119 AC: 809 AN: 67990

Other (OTH) AF: 0.0837 AC: 176 AN: 2102

Alfa AF: 0.0571 Hom.: 215

Bravo AF: 0.103

Asia WGS AF: 0.103 AC: 359 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Benign	0.88
PhyloP100		1.7
PromoterAI		-0.063	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs16954146; hg19: chr17-4618472; COSMIC: COSV52616911; COSMIC: COSV52616911;