chr17-4719402-A-G

Variant names:

• chr17-4719402-A-G
• NM_004313.4:c.899A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS2

The NM_004313.4(ARRB2):​c.899A>G​(p.Asn300Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,560 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ARRB2 NM_004313.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARRB2	NM_004313.4	c.899A>G	p.Asn300Ser	missense_variant	Exon 11 of 15	ENST00000269260.7	NP_004304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARRB2	ENST00000269260.7	c.899A>G	p.Asn300Ser	missense_variant	Exon 11 of 15	1	NM_004313.4	ENSP00000269260.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461560 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727080

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: 0.0000187

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.899A>G (p.N300S) alteration is located in exon 11 (coding exon 11) of the ARRB2 gene. This alteration results from a A to G substitution at nucleotide position 899, causing the asparagine (N) at amino acid position 300 to be replaced by a serine (S). 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	0.25
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;T;.;T;.;.;T;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;.;D;.;D;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.4	M;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.6	D;.;D;.;.;.;.;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.028	D;.;D;.;.;.;.;.
Sift4G	Benign	0.076	T;D;T;D;T;T;D;D
Polyphen		0.93	P;.;P;.;.;.;.;.
Vest4		0.82
MutPred		0.58		Gain of disorder (P = 0.0509);.;.;.;.;.;.;.;
MVP		0.67
MPC		1.7
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.35
gMVP		0.55

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: chr17-4622697;