chr17-4717989-G-A

Position:

• chr17-4717989-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004313.4(ARRB2):​c.587G>A​(p.Arg196Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ARRB2 NM_004313.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24541152).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARRB2	NM_004313.4	c.587G>A	p.Arg196Gln	missense_variant	8/15	ENST00000269260.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARRB2	ENST00000269260.7	c.587G>A	p.Arg196Gln	missense_variant	8/15	1	NM_004313.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461302 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 726930

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2024

The c.587G>A (p.R196Q) alteration is located in exon 8 (coding exon 8) of the ARRB2 gene. This alteration results from a G to A substitution at nucleotide position 587, causing the arginine (R) at amino acid position 196 to be replaced by a glutamine (Q). 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	Benign	0.19
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;.;T;.;.;T;.;T
Eigen	Benign	-0.070
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D;.;D;.;D;D;D;D;D
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.49	N;.;N;.;.;.;.;.;.
REVEL	Benign	0.10
Sift	Benign	0.28	T;.;T;.;.;.;.;.;.
Sift4G	Benign	0.28	T;T;T;T;T;T;T;T;T
Polyphen		0.043	B;.;B;.;.;.;.;.;.
Vest4		0.43
MutPred		0.30		Loss of phosphorylation at S197 (P = 0.1018);.;.;.;.;.;.;Loss of phosphorylation at S197 (P = 0.1018);.;
MVP		0.68
MPC		2.0
ClinPred		0.83	D
GERP RS		4.6
Varity_R		0.083
gMVP		0.54

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: rs1247288395; hg19: chr17-4621284;