Genetic Variant NM_000686.5:c.*1185G>T (chrX-116174557-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000686.5(AGTR2):c.*1185G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0351 in 122,611 control chromosomes in the GnomAD database, including 81 homozygotes. There are 1,226 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.034 ( 74 hom., 1061 hem., cov: 22)

Exomes 𝑓: 0.044 ( 7 hom. 165 hem. )

Consequence

AGTR2
NM_000686.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.13

Publications

2 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.051 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGTR2	NM_000686.5 link	c.*1185G>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000371906.5	NP_000677.2	P50052
AGTR2	NM_001385624.1 link	c.*1185G>T		3_prime_UTR_variant	Exon 2 of 2		NP_001372553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGTR2	ENST00000371906.5 link	c.*1185G>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_000686.5	ENSP00000360973.4		P50052

Frequencies

GnomAD3 genomes

AF:

0.0343

AC:

3814

AN:

111210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00629

Gnomad AMI

AF:

0.0102

Gnomad AMR

AF:

0.0326

Gnomad ASJ

AF:

0.0379

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0147

Gnomad FIN

AF:

0.0476

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0527

Gnomad OTH

AF:

0.0379

GnomAD4 exome

AF:

0.0436

AC:

495

AN:

11347

Hom.:

Cov.:

AF XY:

0.0468

AC XY:

165

AN XY:

3527

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.0437

AC:

489

AN:

11192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0411

AC:

AN:

Other (OTH)

AF:

0.0423

AC:

AN:

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

GnomAD4 genome

AF:

0.0342

AC:

3809

AN:

111264

Hom.:

Cov.:

AF XY:

0.0317

AC XY:

1061

AN XY:

33510

show subpopulations

African (AFR)

AF:

0.00628

AC:

193

AN:

30739

American (AMR)

AF:

0.0326

AC:

339

AN:

10411

Ashkenazi Jewish (ASJ)

AF:

0.0379

AC:

100

AN:

2637

East Asian (EAS)

AF:

0.00

AC:

AN:

3539

South Asian (SAS)

AF:

0.0143

AC:

AN:

2653

European-Finnish (FIN)

AF:

0.0476

AC:

283

AN:

5949

Middle Eastern (MID)

AF:

0.0372

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0526

AC:

2784

AN:

52913

Other (OTH)

AF:

0.0374

AC:

AN:

1524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

143

286

428

571

714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0401

Hom.:

864

Bravo

AF:

0.0338

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.010

(source)

DANN

Benign

0.43

PhyloP100

-1.1

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over