X-116174475-G-C

Variant names:

• chrX-116174475-G-C
• rs12845035
• NM_000686.5:c.*1103G>C

Variant summary

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

The ENST00000371906.5(AGTR2):​c.*1103G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 120,685 control chromosomes in the GnomAD database, including 2,658 homozygotes. There are 8,089 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 0.24 (2377 hom., 7194 hem., cov: 21)
  • Exomes 𝑓: 0.26 (281 hom. 895 hem.)
• Consequence: AGTR2 ENST00000371906.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.481
• Publications: 2 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000371906.5. 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.*1103G>C		3_prime_UTR	Exon 3 of 3	NP_000677.2
	AGTR2	NM_001385624.1		c.*1103G>C		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.*1103G>C		3_prime_UTR	Exon 3 of 3	ENSP00000360973.4

Frequencies

GnomAD3 genomes AF: 0.239 AC: 26095 AN: 109282 Hom.: 2380 Cov.: 21

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.236

Gnomad MID AF: 0.249

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.250

GnomAD4 exome AF: 0.260 AC: 2953 AN: 11353 Hom.: 281 Cov.: 0 AF XY: 0.254 AC XY: 895 AN XY: 3529

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AF: 0.333 AC: 1 AN: 3

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 3

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.261 AC: 2920 AN: 11196

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.200 AC: 15 AN: 75

Other (OTH) AF: 0.208 AC: 15 AN: 72

GnomAD4 genome AF: 0.239 AC: 26093 AN: 109332 Hom.: 2377 Cov.: 21 AF XY: 0.227 AC XY: 7194 AN XY: 31712

African (AFR) AF: 0.262 AC: 7899 AN: 30103

American (AMR) AF: 0.177 AC: 1809 AN: 10224

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 577 AN: 2617

East Asian (EAS) AF: 0.181 AC: 625 AN: 3457

South Asian (SAS) AF: 0.263 AC: 663 AN: 2520

European-Finnish (FIN) AF: 0.236 AC: 1333 AN: 5651

Middle Eastern (MID) AF: 0.251 AC: 54 AN: 215

European-Non Finnish (NFE) AF: 0.241 AC: 12645 AN: 52391

Other (OTH) AF: 0.246 AC: 365 AN: 1485

Alfa AF: 0.118 Hom.: 580

Bravo AF: 0.238

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.13
DANN	Benign	0.42
PhyloP100		-0.48
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: rs12845035; hg19: chrX-115305728;