17-4719350-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_004313.4(ARRB2):​c.847C>T​(p.Arg283Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,614,014 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 0.000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

ARRB2
NM_004313.4 missense

Scores

8
9
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.52
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.839
BS2
High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARRB2NM_004313.4 linkuse as main transcriptc.847C>T p.Arg283Trp missense_variant 11/15 ENST00000269260.7 NP_004304.1 P32121-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARRB2ENST00000269260.7 linkuse as main transcriptc.847C>T p.Arg283Trp missense_variant 11/151 NM_004313.4 ENSP00000269260.2 P32121-1

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152160
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000965
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:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251450
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135902
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
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:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000315
AC:
46
AN:
1461854
Hom.:
0
Cov.:
34
AF XY:
0.0000330
AC XY:
24
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000387
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152160
Hom.:
0
Cov.:
33
AF XY:
0.0000807
AC XY:
6
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.0000965
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:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000526
Hom.:
0
Bravo
AF:
0.0000680
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 21, 2022The c.847C>T (p.R283W) alteration is located in exon 11 (coding exon 11) of the ARRB2 gene. This alteration results from a C to T substitution at nucleotide position 847, causing the arginine (R) at amino acid position 283 to be replaced by a tryptophan (W). 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
0.78
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.55
D;T;.;T;.;.;D;T
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.95
D;.;D;.;D;D;D;D
M_CAP
Uncertain
0.089
D
MetaRNN
Pathogenic
0.84
D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.80
T
MutationAssessor
Pathogenic
3.4
M;.;.;.;.;.;.;.
PrimateAI
Uncertain
0.79
T
PROVEAN
Pathogenic
-6.0
D;.;D;.;.;.;.;.
REVEL
Uncertain
0.56
Sift
Uncertain
0.0010
D;.;D;.;.;.;.;.
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D;D
Polyphen
1.0
D;.;D;.;.;.;.;.
Vest4
0.87
MVP
0.91
MPC
2.0
ClinPred
0.97
D
GERP RS
3.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.61
gMVP
0.77

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs370304415; hg19: chr17-4622645; COSMIC: COSV52619229; COSMIC: COSV52619229; API