5-148826910-G-C

Position:

• chr5-148826910-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000024.6(ADRB2):​c.79G>C​(p.Glu27Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.609 in 1,613,984 control chromosomes in the GnomAD database, including 308,381 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.68 (36699 hom., cov: 34)
  • Exomes 𝑓: 0.60 (271682 hom.)
• Consequence: ADRB2 NM_000024.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.058008E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADRB2	NM_000024.6	c.79G>C	p.Glu27Gln	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.79G>C	p.Glu27Gln	missense_variant	1/1		NM_000024.6	ENSP00000305372	P1

Frequencies

GnomAD3 genomes AF: 0.682 AC: 103807 AN: 152130 Hom.: 36668 Cov.: 34

Gnomad AFR AF: 0.821

Gnomad AMI AF: 0.554

Gnomad AMR AF: 0.757

Gnomad ASJ AF: 0.628

Gnomad EAS AF: 0.910

Gnomad SAS AF: 0.794

Gnomad FIN AF: 0.632

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.568

Gnomad OTH AF: 0.688

GnomAD3 exomes AF: 0.683 AC: 171840 AN: 251422 Hom.: 60932 AF XY: 0.679 AC XY: 92214 AN XY: 135896

Gnomad AFR exome AF: 0.822

Gnomad AMR exome AF: 0.826

Gnomad ASJ exome AF: 0.646

Gnomad EAS exome AF: 0.909

Gnomad SAS exome AF: 0.789

Gnomad FIN exome AF: 0.615

Gnomad NFE exome AF: 0.573

Gnomad OTH exome AF: 0.657

GnomAD4 exome AF: 0.601 AC: 879112 AN: 1461736 Hom.: 271682 Cov.: 67 AF XY: 0.606 AC XY: 440572 AN XY: 727160

Gnomad4 AFR exome AF: 0.829

Gnomad4 AMR exome AF: 0.818

Gnomad4 ASJ exome AF: 0.647

Gnomad4 EAS exome AF: 0.921

Gnomad4 SAS exome AF: 0.787

Gnomad4 FIN exome AF: 0.613

Gnomad4 NFE exome AF: 0.556

Gnomad4 OTH exome AF: 0.629

GnomAD4 genome AF: 0.682 AC: 103899 AN: 152248 Hom.: 36699 Cov.: 34 AF XY: 0.689 AC XY: 51309 AN XY: 74450

Gnomad4 AFR AF: 0.820

Gnomad4 AMR AF: 0.758

Gnomad4 ASJ AF: 0.628

Gnomad4 EAS AF: 0.909

Gnomad4 SAS AF: 0.794

Gnomad4 FIN AF: 0.632

Gnomad4 NFE AF: 0.568

Gnomad4 OTH AF: 0.694

Alfa AF: 0.603 Hom.: 9136

Bravo AF: 0.695

TwinsUK AF: 0.556 AC: 2061

ALSPAC AF: 0.565 AC: 2178

ESP6500AA AF: 0.816 AC: 3597

ESP6500EA AF: 0.580 AC: 4987

ExAC AF: 0.683 AC: 82958

Asia WGS AF: 0.843 AC: 2927 AN: 3478

EpiCase AF: 0.584

EpiControl AF: 0.589

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.77
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	7.1e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.50	N
REVEL	Benign	0.023
Sift	Benign	0.41	T
Sift4G	Benign	0.57	T
Polyphen		0.0090	B
Vest4		0.033
MPC		0.52
ClinPred		0.0077	T
GERP RS		4.0
Varity_R		0.063
gMVP		0.35

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

LitVar

Other links and lift over

dbSNP: rs1042714; hg19: chr5-148206473; COSMIC: COSV60005978;