17-4716538-G-A

Variant names:

• chr17-4716538-G-A
• rs756689239
• NM_004313.4:c.287G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004313.4(ARRB2):​c.287G>A​(p.Arg96Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000358 in 474,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 15)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: ARRB2 NM_004313.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74
• Publications: 2 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11204836).
• BS2: High AC in GnomAdExome4 at 17 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004313.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARRB2	NM_004313.4	MANE Select	c.287G>A	p.Arg96Gln	missense	Exon 5 of 15	NP_004304.1	P32121-1
	ARRB2	NM_001257328.2		c.287G>A	p.Arg96Gln	missense	Exon 5 of 15	NP_001244257.1	P32121-4
	ARRB2	NM_001257330.2		c.287G>A	p.Arg96Gln	missense	Exon 5 of 15	NP_001244259.1	P32121-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARRB2	ENST00000269260.7	TSL:1 MANE Select	c.287G>A	p.Arg96Gln	missense	Exon 5 of 15	ENSP00000269260.2	P32121-1
	ARRB2	ENST00000574954.5	TSL:1	c.-290G>A		5_prime_UTR	Exon 4 of 14	ENSP00000466344.1	Q68DZ5
	ARRB2	ENST00000412477.7	TSL:2	c.287G>A	p.Arg96Gln	missense	Exon 5 of 15	ENSP00000403701.3	P32121-4

Frequencies

GnomAD3 genomes Cov.: 15

GnomAD2 exomes AF: 0.00000959 AC: 2 AN: 208556 AF XY: 0.0000174

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000214

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000358 AC: 17 AN: 474694 Hom.: 0 Cov.: 29 AF XY: 0.0000442 AC XY: 11 AN XY: 249040

African (AFR) AF: 0.00 AC: 0 AN: 13680

American (AMR) AF: 0.00 AC: 0 AN: 32060

Ashkenazi Jewish (ASJ) AF: 0.0000820 AC: 1 AN: 12202

East Asian (EAS) AF: 0.00 AC: 0 AN: 13132

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 53972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1992

European-Non Finnish (NFE) AF: 0.0000495 AC: 15 AN: 302962

Other (OTH) AF: 0.00 AC: 0 AN: 19852

GnomAD4 genome Cov.: 15

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000167 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.7
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.028
Sift	Benign	0.57	T
Sift4G	Benign	0.46	T
Polyphen		0.0040	B
Vest4		0.19
MutPred		0.39		Gain of glycosylation at T99 (P = 0.1093)
MVP		0.37
MPC		2.1
ClinPred		0.56	D
GERP RS		2.8
Varity_R		0.032
gMVP		0.23
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs756689239; hg19: chr17-4619833; COSMIC: COSV52617246; COSMIC: COSV52617246;