chr17-4717989-G-T

Variant names:

• chr17-4717989-G-T
• rs1247288395
• NM_004313.4:c.587G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004313.4(ARRB2):​c.587G>T​(p.Arg196Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R196Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ARRB2 NM_004313.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.58
• Publications: 0 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]

ENSG00000302420 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40786916).

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.587G>T	p.Arg196Leu	missense	Exon 8 of 15	NP_004304.1	P32121-1
	ARRB2	NM_001257328.2		c.650G>T	p.Arg217Leu	missense	Exon 8 of 15	NP_001244257.1	P32121-4
	ARRB2	NM_001257330.2		c.587G>T	p.Arg196Leu	missense	Exon 8 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.587G>T	p.Arg196Leu	missense	Exon 8 of 15	ENSP00000269260.2	P32121-1
	ARRB2	ENST00000574954.5	TSL:1	c.11G>T	p.Arg4Leu	missense	Exon 7 of 14	ENSP00000466344.1	Q68DZ5
	ARRB2	ENST00000412477.7	TSL:2	c.650G>T	p.Arg217Leu	missense	Exon 8 of 15	ENSP00000403701.3	P32121-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461302 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726930

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.13
Sift	Benign	0.070	T
Sift4G	Benign	0.13	T
Polyphen		0.011	B
Vest4		0.65
MutPred		0.32		Loss of disorder (P = 0.0434)
MVP		0.78
MPC		2.0
ClinPred		0.96	D
GERP RS		4.6
Varity_R		0.24
gMVP		0.67

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: rs1247288395; hg19: chr17-4621284; COSMIC: COSV52619383; COSMIC: COSV52619383;