rs121917810

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_000686.5(AGTR2):c.62G>T(p.Gly21Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,208,856 control chromosomes in the GnomAD database, including 13 homozygotes. There are 1,581 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G21R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., 76 hem., cov: 23)

Exomes 𝑓: 0.0042 ( 11 hom. 1505 hem. )

Consequence

AGTR2
NM_000686.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:6

Conservation

PhyloP100: 0.485

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked complex neurodevelopmental disorder
Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

AGTR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0701001).

BP6

Variant X-116172342-G-T is Benign according to our data. Variant chrX-116172342-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 11716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGTR2	NM_000686.5 link	c.62G>T	p.Gly21Val	missense_variant	Exon 3 of 3	ENST00000371906.5	NP_000677.2	P50052
AGTR2	NM_001385624.1 link	c.62G>T	p.Gly21Val	missense_variant	Exon 2 of 2		NP_001372553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AGTR2	ENST00000371906.5 link	c.62G>T	p.Gly21Val	missense_variant	Exon 3 of 3	1	NM_000686.5	ENSP00000360973.4	P50052
AGTR2	ENST00000681852.1 link	c.62G>T	p.Gly21Val	missense_variant	Exon 2 of 2			ENSP00000505750.1	P50052
AGTR2	ENST00000680409.1 link	n.530G>T		non_coding_transcript_exon_variant	Exon 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.00273

AC:

304

AN:

111214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000426

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00335

Gnomad ASJ

AF:

0.00114

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00188

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00837

Gnomad NFE

AF:

0.00453

Gnomad OTH

AF:

0.00401

GnomAD2 exomes

AF:

0.00251

AC:

459

AN:

183135

AF XY:

0.00253

show subpopulations

Gnomad AFR exome

AF:

0.000532

Gnomad AMR exome

AF:

0.00256

Gnomad ASJ exome

AF:

0.00147

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000625

Gnomad NFE exome

AF:

0.00410

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.00417

AC:

4576

AN:

1097590

Hom.:

Cov.:

AF XY:

0.00414

AC XY:

1505

AN XY:

363134

show subpopulations

African (AFR)

AF:

0.000531

AC:

AN:

26375

American (AMR)

AF:

0.00256

AC:

AN:

35140

Ashkenazi Jewish (ASJ)

AF:

0.000878

AC:

AN:

19360

East Asian (EAS)

AF:

0.00

AC:

AN:

30193

South Asian (SAS)

AF:

0.00170

AC:

AN:

54136

European-Finnish (FIN)

AF:

0.000123

AC:

AN:

40519

Middle Eastern (MID)

AF:

0.0104

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00490

AC:

4123

AN:

841668

Other (OTH)

AF:

0.00417

AC:

192

AN:

46065

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

174

347

521

694

868

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

166

332

498

664

830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00271

AC:

301

AN:

111266

Hom.:

Cov.:

AF XY:

0.00227

AC XY:

AN XY:

33552

show subpopulations

African (AFR)

AF:

0.000425

AC:

AN:

30616

American (AMR)

AF:

0.00335

AC:

AN:

10446

Ashkenazi Jewish (ASJ)

AF:

0.00114

AC:

AN:

2631

East Asian (EAS)

AF:

0.00

AC:

AN:

3535

South Asian (SAS)

AF:

0.00113

AC:

AN:

2646

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5967

Middle Eastern (MID)

AF:

0.00917

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00453

AC:

240

AN:

53009

Other (OTH)

AF:

0.00330

AC:

AN:

1515

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00387

Hom.:

204

Bravo

AF:

0.00291

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00588

AC:

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00461

AC:

ExAC

AF:

0.00249

AC:

302

EpiCase

AF:

0.00551

EpiControl

AF:

0.00582

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Aug 08, 2013

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:3

Dec 11, 2015

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jul 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Intellectual disability, X-linked 88

Benign:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

1.7

(source)

DANN

Benign

0.44

DEOGEN2

Benign

0.36

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.37

M_CAP

Benign

0.035

MetaRNN

Benign

0.070

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.34

PhyloP100

0.48

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.35

REVEL

Uncertain

0.37

Sift

Benign

0.20

Sift4G

Benign

0.22

Polyphen

0.0

Vest4

0.055

MVP

0.85

MPC

0.18

ClinPred

0.0015

GERP RS

3.6

Varity_R

0.062

gMVP

0.48

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over