rs35474657

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000686.5(AGTR2):c.971G>A(p.Arg324Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000373 in 1,209,444 control chromosomes in the GnomAD database, including 1 homozygotes. There are 115 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., 58 hem., cov: 22)

Exomes 𝑓: 0.00019 ( 0 hom. 57 hem. )

Consequence

AGTR2
NM_000686.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity no assertion criteria provided U:1B:1

Conservation

PhyloP100: 4.59

Variant links:

Genes affected

AGTR2 (HGNC:338): (angiotensin II receptor type 2) The protein encoded by this gene belongs to the G-protein coupled receptor 1 family, and functions as a receptor for angiotensin II. It is an intergral membrane protein that is highly expressed in fetus and in neonates, but scantily in adult tissues, except brain, adrenal medulla, and atretic ovary. This receptor has been shown to mediate programmed cell death and this apoptotic function may play an important role in developmental biology and pathophysiology. Mutations in this gene are been associated with X-linked cognitive disability. Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and SARS-CoV-2 infection results in down-regulation of angiotensin converting enzyme-2 (ACE2) receptors, the effects of which, triggers serious inflammatory lesions in the tissues involved, primarily in the lungs. The inflammatory reaction appears to be mediated by angiotensin II derivatives, including the angiotensin AT2 receptor which has been found to be upregulated in bronchoalveolar lavage samples from Coronavirus disease 2019 (COVID19) patients. [provided by RefSeq, Jul 2020]

AGTR2 links:

AGTR2 (HGNC:):

AGTR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05501291).

BS2

High Hemizygotes in GnomAd4 at 58 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGTR2	NM_000686.5 linkuse as main transcript	c.971G>A	p.Arg324Gln	missense_variant	3/3	ENST00000371906.5	NP_000677.2	P50052
AGTR2	NM_001385624.1 linkuse as main transcript	c.971G>A	p.Arg324Gln	missense_variant	2/2		NP_001372553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AGTR2	ENST00000371906.5 linkuse as main transcript	c.971G>A	p.Arg324Gln	missense_variant	3/3	1	NM_000686.5	ENSP00000360973.4	P50052
AGTR2	ENST00000681852.1 linkuse as main transcript	c.971G>A	p.Arg324Gln	missense_variant	2/2			ENSP00000505750.1	P50052
AGTR2	ENST00000680409.1 linkuse as main transcript	n.1439G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.00214

AC:

238

AN:

111443

Hom.:

Cov.:

AF XY:

0.00166

AC XY:

AN XY:

33669

show subpopulations

Gnomad AFR

AF:

0.00748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000385

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000377

Gnomad OTH

AF:

0.00203

GnomAD3 exomes

AF:

0.000552

AC:

101

AN:

183068

Hom.:

AF XY:

0.000384

AC XY:

AN XY:

67660

show subpopulations

Gnomad AFR exome

AF:

0.00722

Gnomad AMR exome

AF:

0.000110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.000443

GnomAD4 exome

AF:

0.000192

AC:

211

AN:

1097949

Hom.:

Cov.:

AF XY:

0.000157

AC XY:

AN XY:

363421

show subpopulations

Gnomad4 AFR exome

AF:

0.00713

Gnomad4 AMR exome

AF:

0.000142

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000713

Gnomad4 OTH exome

AF:

0.000239

GnomAD4 genome

AF:

0.00215

AC:

240

AN:

111495

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

AN XY:

33731

show subpopulations

Gnomad4 AFR

AF:

0.00752

Gnomad4 AMR

AF:

0.000384

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000377

Gnomad4 OTH

AF:

0.00200

Alfa

AF:

0.000138

Hom.:

Bravo

AF:

0.00216

ESP6500AA

AF:

0.00730

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000692

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Aug 08, 2013

- -

AGTR2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 23, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.76

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.17

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.79

M_CAP

Benign

0.0024

MetaRNN

Benign

0.055

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.34

PROVEAN

Benign

0.0

REVEL

Benign

0.086

Sift

Benign

0.83

Sift4G

Benign

0.68

Polyphen

0.012

Vest4

0.082

MVP

0.82

MPC

0.16

ClinPred

0.016

GERP RS

1.7

Varity_R

0.19

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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