X-116173577-A-G

Variant names:

• chrX-116173577-A-G
• rs5194
• NM_000686.5:c.*205A>G

Variant summary

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

The NM_000686.5(AGTR2):​c.*205A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. 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 0.51 (10440 hom., 16684 hem., cov: 23)
  • Exomes 𝑓: 0.55 (38837 hom. 61580 hem.)
  • Failed GnomAD Quality Control
• Consequence: AGTR2 NM_000686.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.16
• Publications: 24 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=-0.88).
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000686.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGTR2	NM_000686.5	MANE Select	c.*205A>G		3_prime_UTR	Exon 3 of 3	NP_000677.2
	AGTR2	NM_001385624.1		c.*205A>G		3_prime_UTR	Exon 2 of 2	NP_001372553.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGTR2	ENST00000371906.5	TSL:1 MANE Select	c.*205A>G		3_prime_UTR	Exon 3 of 3	ENSP00000360973.4
	AGTR2	ENST00000681852.1		c.*205A>G		downstream_gene	N/A	ENSP00000505750.1
	AGTR2	ENST00000680409.1		n.*147A>G		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.507 AC: 56215 AN: 110787 Hom.: 10438 Cov.: 23

Gnomad AFR AF: 0.396

Gnomad AMI AF: 0.556

Gnomad AMR AF: 0.637

Gnomad ASJ AF: 0.543

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.504

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.535

GnomAD4 exome AF: 0.546 AC: 204045 AN: 373677 Hom.: 38837 Cov.: 5 AF XY: 0.565 AC XY: 61580 AN XY: 109045

African (AFR) AF: 0.411 AC: 4239 AN: 10322

American (AMR) AF: 0.654 AC: 8680 AN: 13264

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 5406 AN: 9830

East Asian (EAS) AF: 0.626 AC: 14029 AN: 22422

South Asian (SAS) AF: 0.499 AC: 11979 AN: 24016

European-Finnish (FIN) AF: 0.536 AC: 16800 AN: 31339

Middle Eastern (MID) AF: 0.552 AC: 767 AN: 1390

European-Non Finnish (NFE) AF: 0.545 AC: 131025 AN: 240609

Other (OTH) AF: 0.543 AC: 11120 AN: 20485

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.507 AC: 56232 AN: 110838 Hom.: 10440 Cov.: 23 AF XY: 0.504 AC XY: 16684 AN XY: 33080

African (AFR) AF: 0.396 AC: 12141 AN: 30665

American (AMR) AF: 0.638 AC: 6599 AN: 10339

Ashkenazi Jewish (ASJ) AF: 0.543 AC: 1424 AN: 2623

East Asian (EAS) AF: 0.590 AC: 2044 AN: 3467

South Asian (SAS) AF: 0.464 AC: 1255 AN: 2705

European-Finnish (FIN) AF: 0.530 AC: 3114 AN: 5873

Middle Eastern (MID) AF: 0.498 AC: 105 AN: 211

European-Non Finnish (NFE) AF: 0.538 AC: 28369 AN: 52777

Other (OTH) AF: 0.536 AC: 812 AN: 1514

Alfa AF: 0.526 Hom.: 58439

Bravo AF: 0.515

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.34
DANN	Benign	0.70
PhyloP100		-1.2
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: rs5194; hg19: chrX-115304830; COSMIC: COSV64156414;