chr5-148827322-C-T

Position:

• chr5-148827322-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000024.6(ADRB2):​c.491C>T​(p.Thr164Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,614,130 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0090 (10 hom., cov: 33)
  • Exomes 𝑓: 0.012 (148 hom.)
• Consequence: ADRB2 NM_000024.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 3.11

Genes affected

ADRB2 (HGNC:286): (adrenoceptor beta 2) This gene encodes beta-2-adrenergic receptor which is a member of the G protein-coupled receptor superfamily. This receptor is directly associated with one of its ultimate effectors, the class C L-type calcium channel Ca(V)1.2. This receptor-channel complex also contains a G protein, an adenylyl cyclase, cAMP-dependent kinase, and the counterbalancing phosphatase, PP2A. The assembly of the signaling complex provides a mechanism that ensures specific and rapid signaling by this G protein-coupled receptor. This receptor is also a transcription regulator of the alpha-synuclein gene, and together, both genes are believed to be associated with risk of Parkinson's Disease. This gene is intronless. Different polymorphic forms, point mutations, and/or downregulation of this gene are associated with nocturnal asthma, obesity, type 2 diabetes and cardiovascular disease. [provided by RefSeq, Oct 2019]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0117586255).
• BP6: Variant 5-148827322-C-T is Benign according to our data. Variant chr5-148827322-C-T is described in ClinVar as [Benign]. Clinvar id is 17744.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 1377 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADRB2	NM_000024.6	c.491C>T	p.Thr164Ile	missense_variant	1/1	ENST00000305988.6	NP_000015.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADRB2	ENST00000305988.6	c.491C>T	p.Thr164Ile	missense_variant	1/1		NM_000024.6	ENSP00000305372	P1

Frequencies

GnomAD3 genomes AF: 0.00905 AC: 1378 AN: 152190 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0134

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00907 AC: 2281 AN: 251490 Hom.: 21 AF XY: 0.00962 AC XY: 1307 AN XY: 135920

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00720

Gnomad ASJ exome AF: 0.00853

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00405

Gnomad FIN exome AF: 0.00494

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.0125 AC: 18200 AN: 1461822 Hom.: 148 Cov.: 54 AF XY: 0.0121 AC XY: 8778 AN XY: 727212

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.00770

Gnomad4 ASJ exome AF: 0.00719

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00409

Gnomad4 FIN exome AF: 0.00509

Gnomad4 NFE exome AF: 0.0144

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.00904 AC: 1377 AN: 152308 Hom.: 10 Cov.: 33 AF XY: 0.00819 AC XY: 610 AN XY: 74474

Gnomad4 AFR AF: 0.00245

Gnomad4 AMR AF: 0.0134

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00330

Gnomad4 NFE AF: 0.0141

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.0127 Hom.: 30

Bravo AF: 0.00953

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0156 AC: 60

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0150 AC: 129

ExAC AF: 0.00945 AC: 1148

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0136

EpiControl AF: 0.0158

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

ADRB2: BS1, BS2 -

Beta-2-adrenoreceptor agonist, reduced response to Other:1

drug response, no assertion criteria provided

literature only

OMIM

Aug 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.065
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.1	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.17
Sift	Benign	0.59	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.60
MPC		0.57
ClinPred		0.027	T
GERP RS		5.7
Varity_R		0.57
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs1800888; hg19: chr5-148206885;