rs5193

Variant names:

• chrX-116173571-G-T
• rs5193
• NM_000686.5:c.*199G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000686.5(AGTR2):​c.*199G>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 0.243 in 512,637 control chromosomes in the GnomAD database, including 11,781 homozygotes. There are 36,739 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 0.19 (1881 hom., 6610 hem., cov: 23)
  • Exomes 𝑓: 0.26 (9900 hom. 30129 hem.)
• Consequence: AGTR2 NM_000686.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.375
• Publications: 21 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGTR2	NM_000686.5	c.*199G>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000371906.5	NP_000677.2
AGTR2	NM_001385624.1	c.*199G>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	c.*199G>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_000686.5	ENSP00000360973.4
AGTR2	ENST00000681852.1	c.*199G>T		downstream_gene_variant				ENSP00000505750.1
AGTR2	ENST00000680409.1	n.*141G>T		downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.194 AC: 21552 AN: 111366 Hom.: 1880 Cov.: 23

Gnomad AFR AF: 0.0345

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.258

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.209

GnomAD4 exome AF: 0.257 AC: 103175 AN: 401218 Hom.: 9900 Cov.: 6 AF XY: 0.274 AC XY: 30129 AN XY: 109926

African (AFR) AF: 0.0370 AC: 403 AN: 10901

American (AMR) AF: 0.204 AC: 2767 AN: 13589

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 2775 AN: 10046

East Asian (EAS) AF: 0.179 AC: 4065 AN: 22652

South Asian (SAS) AF: 0.192 AC: 4687 AN: 24459

European-Finnish (FIN) AF: 0.375 AC: 11881 AN: 31666

Middle Eastern (MID) AF: 0.285 AC: 408 AN: 1430

European-Non Finnish (NFE) AF: 0.268 AC: 70954 AN: 264942

Other (OTH) AF: 0.243 AC: 5235 AN: 21533

GnomAD4 genome AF: 0.193 AC: 21547 AN: 111419 Hom.: 1881 Cov.: 23 AF XY: 0.196 AC XY: 6610 AN XY: 33651

African (AFR) AF: 0.0344 AC: 1065 AN: 30930

American (AMR) AF: 0.205 AC: 2134 AN: 10419

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 689 AN: 2629

East Asian (EAS) AF: 0.154 AC: 543 AN: 3520

South Asian (SAS) AF: 0.176 AC: 481 AN: 2727

European-Finnish (FIN) AF: 0.380 AC: 2238 AN: 5894

Middle Eastern (MID) AF: 0.274 AC: 58 AN: 212

European-Non Finnish (NFE) AF: 0.261 AC: 13822 AN: 52898

Other (OTH) AF: 0.207 AC: 315 AN: 1523

Alfa AF: 0.238 Hom.: 12398

Bravo AF: 0.178

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.62
DANN	Benign	0.61
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5193; hg19: chrX-115304824;