rs3736556

Variant names:

• chrX-116171082-A-T
• rs3736556
• NM_000686.5:c.-36+55A>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.-36+55A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 110,701 control chromosomes in the GnomAD database, including 2,012 homozygotes. There are 6,603 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 0.21 (2012 hom., 6603 hem., cov: 23)
  • Failed GnomAD Quality Control
• Consequence: AGTR2 NM_000686.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.47
• Publications: 5 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGTR2	NM_000686.5	c.-36+55A>T		intron_variant	Intron 2 of 2	ENST00000371906.5	NP_000677.2
AGTR2	NM_001385624.1	c.-36+266A>T		intron_variant	Intron 1 of 1		NP_001372553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGTR2	ENST00000371906.5	c.-36+55A>T		intron_variant	Intron 2 of 2	1	NM_000686.5	ENSP00000360973.4
AGTR2	ENST00000681852.1	c.-36+266A>T		intron_variant	Intron 1 of 1			ENSP00000505750.1

Frequencies

GnomAD3 genomes AF: 0.210 AC: 23201 AN: 110650 Hom.: 2014 Cov.: 23

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.252

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.243

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.210 AC: 23199 AN: 110701 Hom.: 2012 Cov.: 23 AF XY: 0.200 AC XY: 6603 AN XY: 33015

African (AFR) AF: 0.113 AC: 3476 AN: 30739

American (AMR) AF: 0.169 AC: 1757 AN: 10401

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 616 AN: 2633

East Asian (EAS) AF: 0.186 AC: 645 AN: 3471

South Asian (SAS) AF: 0.240 AC: 638 AN: 2663

European-Finnish (FIN) AF: 0.252 AC: 1462 AN: 5792

Middle Eastern (MID) AF: 0.265 AC: 57 AN: 215

European-Non Finnish (NFE) AF: 0.267 AC: 14054 AN: 52610

Other (OTH) AF: 0.241 AC: 362 AN: 1505

Alfa AF: 0.240 Hom.: 1487

Bravo AF: 0.200

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.3
DANN	Benign	0.72
PhyloP100		1.5
PromoterAI		-0.0017	Neutral
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: rs3736556; hg19: chrX-115302335;