Genetic Variant NM_000024.6:c.491C>T (chr5-148827322-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

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

Scores

Clinical Significance

Benign criteria provided, single submitter B:1O:1

Conservation

PhyloP100: 3.11

Variant links:

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]

ADRB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
ADRB2	NM_000024.6 link	c.491C>T	p.Thr164Ile	missense_variant	Exon 1 of 1	ENST00000305988.6	NP_000015.2	P07550X5DQM5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADRB2	ENST00000305988.6 link	c.491C>T	p.Thr164Ile	missense_variant	Exon 1 of 1	6	NM_000024.6	ENSP00000305372.4		P07550

Frequencies

GnomAD3 genomes

AF:

0.00905

AC:

1378

AN:

152190

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00962

AC XY:

1307

AN XY:

135920

show subpopulations

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.:

AF XY:

0.0121

AC XY:

8778

AN XY:

727212

show subpopulations

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.:

Cov.:

AF XY:

0.00819

AC XY:

610

AN XY:

74474

show subpopulations

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.:

Bravo

AF:

0.00953

TwinsUK

AF:

0.0135

AC:

ALSPAC

AF:

0.0156

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0150

AC:

129

ExAC

AF:

0.00945

AC:

1148

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0136

EpiControl

AF:

0.0158

ClinVar

Significance: Benign

Submissions summary: Benign:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ADRB2: BS1, BS2 -

Beta-2-adrenoreceptor agonist, reduced response to

Other:1

Aug 01, 2004

OMIM

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.090

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.065

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-1.1

PrimateAI

Uncertain

0.52

PROVEAN

Benign

2.1

REVEL

Benign

0.17

Sift

Benign

0.59

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.12

MVP

0.60

MPC

0.57

ClinPred

0.027

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over