chr17-4718286-A-T

Variant names:

• chr17-4718286-A-T
• NM_004313.4:c.647A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004313.4(ARRB2):​c.647A>T​(p.Asn216Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,234 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARRB2 NM_004313.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.694

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20215732).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARRB2	NM_004313.4	c.647A>T	p.Asn216Ile	missense_variant	Exon 9 of 15	ENST00000269260.7	NP_004304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARRB2	ENST00000269260.7	c.647A>T	p.Asn216Ile	missense_variant	Exon 9 of 15	1	NM_004313.4	ENSP00000269260.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460234 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726192

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.35
DANN	Benign	0.87
DEOGEN2	Uncertain	0.43	T;T;.;T;.;.;T;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.66	T;.;T;.;T;T;T;T;T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.5	N;.;N;.;.;.;.;.;.
REVEL	Benign	0.064
Sift	Benign	0.084	T;.;T;.;.;.;.;.;.
Sift4G	Benign	0.15	T;T;T;T;T;T;T;T;T
Polyphen		0.0060	B;.;B;.;.;.;.;.;.
Vest4		0.45
MutPred		0.46		Loss of catalytic residue at N216 (P = 0.0203);.;.;.;.;.;.;Loss of catalytic residue at N216 (P = 0.0203);.;
MVP		0.48
MPC		1.1
ClinPred		0.15	T
GERP RS		-2.4
Varity_R		0.11
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-4621581;