rs748931059

Variant names:

• chr17-4716186-G-A
• rs748931059
• NM_004313.4:c.155G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_004313.4(ARRB2):​c.155G>A​(p.Arg52His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: ARRB2 NM_004313.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.18

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 Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809
• BS2: High AC in GnomAdExome4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARRB2	NM_004313.4	c.155G>A	p.Arg52His	missense_variant	Exon 4 of 15	ENST00000269260.7	NP_004304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARRB2	ENST00000269260.7	c.155G>A	p.Arg52His	missense_variant	Exon 4 of 15	1	NM_004313.4	ENSP00000269260.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251442 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461796 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74468

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000141 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.155G>A (p.R52H) alteration is located in exon 4 (coding exon 4) of the ARRB2 gene. This alteration results from a G to A substitution at nucleotide position 155, causing the arginine (R) at amino acid position 52 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	T;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Pathogenic	3.6	H;H;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.9	D;.;.
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.66
MutPred		0.76		Loss of stability (P = 0.0679);Loss of stability (P = 0.0679);Loss of stability (P = 0.0679);
MVP		0.83
MPC		2.2
ClinPred		0.99	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.63
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs748931059; hg19: chr17-4619481; COSMIC: COSV52619501; COSMIC: COSV52619501;